Wednesday, December 28, 2016

Results from Drosophila contribute to study of the neurodevelopmental disorder Vici syndrome

Byrne S, Jansen L, U-King-Im JM, Siddiqui A, Lidov HG, Bodi I, Smith L, Mein R, Cullup T, Dionisi-Vici C, Al-Gazali L, Al-Owain M, Bruwer Z, Al Thihli K, El-Garhy R, Flanigan KM, Manickam K, Zmuda E, Banks W, Gershoni-Baruch R, Mandel H, Dagan E, Raas-Rothschild A, Barash H, Filloux F, Creel D, Harris M, Hamosh A, Kölker S, Ebrahimi-Fakhari D, Hoffmann GF, Manchester D, Boyer PJ, Manzur AY, Lourenco CM, Pilz DT, Kamath A, Prabhakar P, Rao VK, Rogers RC, Ryan MM, Brown NJ, McLean CA, Said E, Schara U, Stein A, Sewry C, Travan L, Wijburg FA, Zenker M, Mohammed S, Fanto M, Gautel M, Jungbluth H. EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy. Brain. 2016 Mar;139(Pt 3):765-81. doi: 10.1093/brain/awv393. PubMed PMID: 26917586; PubMed Central PMCID: PMC4766378.

From the abstract: "Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. ... Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease."

Results of genetic and human transgene analyses in Drosophila contributes to study of XX gonadal dysgenesis

Weinberg-Shukron A, Renbaum P, Kalifa R, Zeligson S, Ben-Neriah Z, Dreifuss A, Abu-Rayyan A, Maatuk N, Fardian N, Rekler D, Kanaan M, Samson AO, Levy-Lahad E, Gerlitz O, Zangen D. A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis. J Clin Invest. 2015 Nov 2;125(11):4295-304. doi: 10.1172/JCI83553. PubMed PMID: 26485283; PubMed Central PMCID: PMC4639971.

From the abstract: "... XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder that is characterized by underdeveloped, dysfunctional ovaries ... Here, we report an extended consanguineous family .. in which 4 females exhibited XX-GD. ... we identified a recessive missense mutation in nucleoporin-107 (NUP107, c.1339G>A, p.D447N). ... NUP107 is a component of the nuclear pore complex ... In Drosophila, Nup107 knockdown in somatic gonadal cells resulted in female sterility, whereas males were fully fertile. Transgenic rescue of Drosophila females bearing the Nup107D364N mutation, which corresponds to the human NUP107 (p.D447N), resulted in almost complete sterility ..."

Flies used in a study related to understanding and treating hydrogen sulfide toxicity

Jiang J, Chan A, Ali S, Saha A, Haushalter KJ, Lam WL, Glasheen M, Parker J, Brenner M, Mahon SB, Patel HH, Ambasudhan R, Lipton SA, Pilz RB, Boss GR. Hydrogen Sulfide--Mechanisms of Toxicity and Development of an Antidote. Sci Rep. 2016 Feb 15;6:20831. PMID: 26877209; PMCID: PMC4753484.

From the abstract: "Hydrogen sulfide is a highly toxic gas-second only to carbon monoxide as a cause of inhalational deaths. Its mechanism of toxicity is only partially known, and no specific therapy exists for sulfide poisoning. ... The vitamin B12 analog cobinamide reversed the cellular toxicity of sulfide, and rescued Drosophila melanogaster and mice from lethal exposures of hydrogen sulfide gas. ... We conclude that sulfide produces a high degree of oxidative stress in cells and tissues, and that cobinamide has promise as a first specific treatment for sulfide poisoning."

Tuesday, December 27, 2016

Drosophila modeling part of a study of autosomal recessive cerebellar ataxia

Duan R, Shi Y, Yu L, Zhang G, Li J, Lin Y, Guo J, Wang J, Shen L, Jiang H, Wang G, Tang B. UBA5 Mutations Cause a New Form of Autosomal Recessive Cerebellar Ataxia. PLoS One. 2016 Feb 12;11(2):e0149039. PMID: 26872069; PMCID: PMC4752235.

From the abstract: "Autosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. For many affected patients, the genetic cause remains undetermined. Through whole-exome sequencing, we identified compound heterozygous mutations in ubiquitin-like modifier activating enzyme 5 gene (UBA5) in two Chinese siblings presenting with ARCA. ... Drosophila modeling revealed that UBA5 knockdown induced locomotive defects and a shortened lifespan accompanied by aberrant neuromuscular junctions (NMJs). ... The finding of a UBA5 mutation in cerebellar ataxia suggests that impairment of the UFM1 pathway may contribute to the neurological phenotypes of ARCA."

Genetic modifier screen with a fly model of ALS/FTD

Boeynaems S, Bogaert E, Michiels E, Gijselinck I, Sieben A, Jovičić A, De Baets G, Scheveneels W, Steyaert J, Cuijt I, Verstrepen KJ, Callaerts P, Rousseau F, Schymkowitz J, Cruts M, Van Broeckhoven C, Van Damme P, Gitler AD, Robbenecht W, Van Den Bosch L. Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD. Sci Rep. 2016 Feb 12;6:20877. PMID: 26869068; PMCID: PMC4751451.

From the abstract: "Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). ... We performed a modifier screen in Drosophila and discovered a critical role for importins and exportins, Ran-GTP cycle regulators, nuclear pore components, and arginine methylases in mediating DPR toxicity. These findings provide evidence for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD."

Fly cell and in vivo study of responses to lithium and valproate

Herteleer L, Zwarts L, Hens K, Forero D, Del-Favero J, Callaerts P. Mood stabilizing drugs regulate transcription of immune, neuronal and metabolic pathway genes in Drosophila. Psychopharmacology (Berl). 2016 May;233(9):1751-62. PMID: 26852229.

From the abstract: "Lithium and valproate (VPA) are drugs used in the management of bipolar disorder. ... We used Drosophila culture cells and adult flies to analyze the transcriptional effects of lithium and VPA and define mechanistic pathways. ... Transcriptional profiles were determined for Drosophila S2-cells and adult fly heads following lithium or VPA treatment. ... Lithium and VPA act on evolutionarily conserved pathways in Drosophila and mammalian models."

Using flies to learn information related to Fragile X syndrome

Doll CA, Broadie K. Neuron class-specific requirements for Fragile X Mental Retardation Protein in critical period development of calcium signaling in learning and memory circuitry. Neurobiol Dis. 2016 May;89:76-87. PMID: 26851502; PMCID: PMC4785039.

From the abstract: "... Fragile X Mental Retardation Protein (FMRP), the gene product lost in Fragile X syndrome (FXS), acts as an activity sensor during critical period development, both as an RNA-binding translation regulator and channel-binding excitability regulator. Here, we employ a Drosophila FXS disease model to assay calcium signaling dynamics with a targeted transgenic GCaMP reporter during critical period development of the mushroom body (MB) learning/memory circuit. We find FMRP regulates depolarization-induced calcium signaling in a neuron-specific manner within this circuit, suppressing activity-dependent calcium transients in excitatory cholinergic MB input projection neurons and enhancing calcium signals in inhibitory GABAergic MB output neurons. ... These results show FMRP shapes neuron class-specific calcium signaling in excitatory vs. inhibitory neurons in developing learning/memory circuitry, and that FMRP mediates activity-dependent regulation of calcium signaling specifically during the early-use critical period."

Doll CA, Broadie K. Activity-dependent FMRP requirements in development of the neural circuitry of learning and memory. Development. 2015 Apr 1;142(7):1346-56. PMID: 25804740; PMCID: PMC4378248.

From the abstract: "... Here, we use optogenetic tools in the Drosophila FXS disease model to test activity-dependent dendritogenesis in two extrinsic neurons of the mushroom body (MB) learning and memory brain center: (1) the input projection neuron (PN) innervating Kenyon cells (KCs) in the MB calyx microglomeruli and (2) the output MVP2 neuron innervated by KCs in the MB peduncle. Both input and output neuron classes exhibit distinctive activity-dependent critical period dendritic remodeling. MVP2 arbors expand in Drosophila mutants null for fragile X mental retardation 1 (dfmr1), as well as following channelrhodopsin-driven depolarization during critical period development, but are reduced by halorhodopsin-driven hyperpolarization. ... results show that dfmr1 acts in a neuron type-specific activity-dependent manner for sculpting dendritic arbors during early-use, critical period development of learning and memory circuitry in the Drosophila brain."

Fly model of Alexander disease used in screen of FDA-approved drugs

Wang L, Hagemann TL, Messing A, Feany MB. An In Vivo Pharmacological Screen Identifies Cholinergic Signaling as a Therapeutic Target in Glial-Based Nervous System Disease. J Neurosci. 2016 Feb 3;36(5):1445-55. PMID: 26843629; PubMed PMC4737762.

From the abstract: "... Here we use a simple genetic model of Alexander disease, a progressive and severe human degenerative nervous system disease ... to perform an in vivo screen of 1987 compounds, including many FDA-approved drugs and natural products. We identify four compounds capable of dose-dependent inhibition of nervous system toxicity. Focusing on one of these hits, glycopyrrolate, we confirm the role for muscarinic cholinergic signaling in pathogenesis using additional pharmacologic reagents and genetic approaches. ... We have therefore identified glial muscarinic signaling as a potential therapeutic target in Alexander disease, and possibly in other gliopathic disorders as well.

From the significance statement: "Despite the urgent need for better treatments for neurological diseases, drug development for these devastating disorders has been challenging. The effectiveness of traditional large-scale in vitro screens may be limited by the lack of the appropriate molecular, cellular, and structural environment. Using a simple Drosophila model of Alexander disease, we performed a moderate throughput chemical screen of FDA-approved drugs and natural compounds... Our work demonstrates that small animal models are valuable screening tools for therapeutic compound identification in complex human diseases and that existing drugs can be a valuable resource for drug discovery given their known pharmacological and safety profiles."

Review: Fly model in evaluation of therapeutics for mitochondrial diseases

Foriel S, Willems P, Smeitink J, Schenck A, Beyrath J. Mitochondrial diseases: Drosophila melanogaster as a model to evaluate potential therapeutics. Int J Biochem Cell Biol. 2015 Jun;63:60-5. PMID: 25666557.

From the abstract: "... mitochondrial diseases comprise a wide range of clinical, biochemical and genetic heterogeneous disorders. ... Despite intense research efforts, patients are still without effective treatment. An important part of the development of new therapeutics relies on predictive models of the pathology in order to assess their therapeutic potential. ... Here, we review existing Drosophila melanogaster models for mitochondrial diseases, with a focus on alterations in oxidative phosphorylation, and discuss the potential of this powerful model organism in the process of drug target discovery ..."

Learning from a fly model of traumatic brain injury

Katzenberger RJ, Chtarbanova S, Rimkus SA, Fischer JA, Kaur G, Seppala JM, Swanson LC, Zajac JE, Ganetzky B, Wassarman DA. Death following traumatic brain injury in Drosophila is associated with intestinal barrier dysfunction. Elife.2015 Mar 5;4. PMID: 25742603; PMCID: PMC4377547.

From the abstract: "Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Unfavorable TBI outcomes result from primary mechanical injuries to the brain and ensuing secondary non-mechanical injuries that are not limited to the brain. Our genome-wide association study of Drosophila melanogaster revealed that the probability of death following TBI is associated with single nucleotide polymorphisms in genes involved in tissue barrier function and glucose homeostasis. We found that TBI causes intestinal and blood-brain barrier dysfunction and that intestinal barrier dysfunction is highly correlated with the probability of death. ..."

Friday, December 16, 2016

Fly wing disc tissue used to study neurodegenerative disease-related cellular activities

Bougé AL, Parmentier ML. Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death. Dis Model Mech. 2016 Mar;9(3):307-19. PMID: 26822478; PMCID: PMC4833329.

From the abstract: "In neurodegenerative diseases such as Alzheimer's disease (AD), cell cycle defects and associated aneuploidy have been described. However, the importance of these defects in the physiopathology of AD and the underlying mechanistic processes are largely unknown... Here, we studied the effect of an excess of human Tau (hTau) protein on cell mitosis in vivo. Using the Drosophila developing wing disc epithelium as a model, we show that an excess of hTau induces a mitotic arrest, with the presence of monopolar spindles. This mitotic defect leads to aneuploidy and apoptotic cell death. We studied the mechanism of action of hTau and found that the MT-binding domain of hTau is responsible for these defects. ... We finally show that this deleterious effect of hTau is also found in other Drosophila cell types (neuroblasts) and tissues (the developing eye disc), as well as in human HeLa cells. By demonstrating that MT-bound Tau inhibits the Eg5 kinesin and cell mitosis, our work provides a new framework to consider the role of Tau in neurodegenerative diseases."

Results from Drosophila help point to changes in TANGO2 as causative for an infancy-onset metabolic disorder

Kremer LS, Distelmaier F, Alhaddad B, Hempel M, Iuso A, Küpper C, Mühlhausen C, Kovacs-Nagy R, Satanovskij R, Graf E, Berutti R, Eckstein G, Durbin R, Sauer S, Hoffmann GF, Strom TM, Santer R, Meitinger T, Klopstock T, Prokisch H, Haack TB. Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy. Am J Hum Genet. 2016 Feb 4;98(2):358-62. PMID: 26805782; PMCID: PMC4746337.

From the abstract: "Molecular diagnosis of mitochondrial disorders is challenging because of extreme clinical and genetic heterogeneity. By exome sequencing, we identified three different bi-allelic truncating mutations in TANGO2 in three unrelated individuals with infancy-onset episodic metabolic crises ... TANGO2 (transport and Golgi organization 2) encodes a protein with a putative function in redistribution of Golgi membranes into the endoplasmic reticulum in Drosophila and a mitochondrial localization has been confirmed in mice. ... Our results establish TANGO2 deficiency as a clinically recognizable cause of pediatric disease with multi-organ involvement."

Evidence from mammalian cells and Drosophila model contributes to a study related to Down syndrome and Fragile X syndrome

Sterne GR, Kim JH, Ye B. Dysregulated Dscam levels act through Abelson tyrosine kinase to enlarge presynaptic arbors. Elife. 2015 May 19;4. PMID: 25988807; PMCID: PMC4434255.

The abstract: "Increased expression of Down Syndrome Cell Adhesion Molecule (Dscam) is implicated in the pathogenesis of brain disorders such as Down syndrome (DS) and fragile X syndrome (FXS). Here, we show that the cellular defects caused by dysregulated Dscam levels can be ameliorated by genetic and pharmacological inhibition of Abelson kinase (Abl) both in Dscam-overexpressing neurons and in a Drosophila model of fragile X syndrome. This study offers Abl as a potential therapeutic target for treating brain disorders associated with dysregulated Dscam expression."

"Independent functional evidence in Drosophila" contributes to study related to intellectual disability

Lugtenberg D, Reijnders MR, Fenckova M, Bijlsma EK, Bernier R, van Bon BW, Smeets E, Vulto-van Silfhout AT, Bosch D, Eichler EE, Mefford HC, Carvill GL, Bongers EM, Schuurs-Hoeijmakers JH, Ruivenkamp CA, Santen GW, van den Maagdenberg AM, Peeters-Scholte CM, Kuenen S, Verstreken P, Pfundt R, Yntema HG, de Vries PF, Veltman JA, Hoischen A, Gilissen C, de Vries BB, Schenck A, Kleefstra T, Vissers LE. De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila. Eur J Hum Genet. 2016 Aug;24(8):1145-53. PMID: 26757981; PMCID: PMC4970694.

From the abstract: "Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. ... In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. ... To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification."

Review of Drosophila and other invertebrate models of Tauopathies

Hannan SB, Dräger NM, Rasse TM, Voigt A, Jahn TR. Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models. J Neurochem. 2016 Apr;137(1):12-25. PMID: 26756400.

From the abstract: "Abnormal tau accumulations were observed and documented in post-mortem brains of patients affected by Alzheimer's disease (AD) ... An important discovery came with the demonstration that over-expression of human tau in Drosophila leads to premature mortality and neuronal dysfunction including neurodegeneration, recapitulating some key neuropathological features of the human disease. ... We discuss the utility and application of invertebrate models in elucidating the cellular and molecular functions of novel and uncharacterized disease modifiers identified in large-scale screens as well as for investigating the function of genes identified as risk factors in genome-wide association studies from human patients in the post-genomic era. ..."

Introduction of disease-associated mutations in Drosophila orthologs of genes linked to myopathy and muscular dystrophy

Li S, Zhang P, Freibaum BD, Kim NC, Kolaitis RM, Molliex A, Kanagaraj AP, Yabe I, Tanino M, Tanaka S, Sasaki H, Ross ED, Taylor JP, Kim HJ. Genetic interaction of hnRNPA2B1 and DNAJB6 in a Drosophila model of multisystem proteinopathy. Hum Mol Genet. 2016 Mar 1;25(5):936-50. PMID: 26744327; PMCID: PMC4754048.

From the abstract: "Adult-onset inherited myopathies with similar pathological features, including hereditary inclusion body myopathy (hIBM) and limb-girdle muscular dystrophy (LGMD), are a genetically heterogeneous group of muscle diseases. ... Here, we exploit a genetic model system to establish a mechanistic link between diseases caused by mutations in two distinct genes, hnRNPA2B1 and DNAJB6. Hrb98DE and mrj are the Drosophila melanogaster homologs of human hnRNPA2B1 and DNAJB6, respectively. We introduced disease-homologous mutations to Hrb98DE, thus capturing mutation-dependent phenotypes in a genetically tractable model system. ... These results indicate both genetic and physical interactions between disease-linked RBPs and DNAJB6/mrj, suggesting etiologic overlap between the pathogenesis of hIBM and LGMD initiated by mutations in hnRNPA2B1 and DNAJB6."

Thursday, December 15, 2016

Review highlights use of mouse, fly, and other model organisms to study Menkes disease

Lenartowicz M, Krzeptowski W, Lipiński P, Grzmil P, Starzyński R, Pierzchała O, Møller LB. Mottled Mice and Non-Mammalian Models of Menkes Disease. Front Mol Neurosci. 2015 Dec 18;8:72. PMID: 26732058; PMCID: PMC4684000.

From the abstract: "Menkes disease is a multi-systemic copper metabolism disorder caused by mutations in the X-linked ATP7A gene and characterized by progressive neurodegeneration and severe connective tissue defects. .... Mottled mutants closely recapitulate the Menkes phenotype and are invaluable for studying Cu-metabolism. They provide useful models for exploring and testing new forms of therapy in Menkes disease. Recently, non-mammalian models of Menkes disease, Drosophila melanogaster and Danio rerio mutants were used in experiments which would be technically difficult to carry out in mammals."

Review -- Relevance of circadian rhythm gene Timeless to human health and disease

Mazzoccoli G, Laukkanen MO, Vinciguerra M, Colangelo T, Colantuoni V. A Timeless Link Between Circadian Patterns and Disease. Trends Mol Med. 2016 Jan;22(1):68-81. PMID: 26691298.

From the abstract: "The Timeless (Tim) gene, originally identified in Drosophila melanogaster and subsequently in mammals, is involved in the molecular clockwork that drives 24h periodicity in physiology and behavior. The Tim protein is ... a multifaceted factor implicated in the maintenance of many cellular processes, tissue functions, and ultimately homeostasis of various organisms, from insects to humans. This review highlights the current knowledge of Tim functions, especially the most recent achievements, and illustrates the possible roles that this factor plays in the physiological preservation of health, as well as in the pathogenic mechanisms of related diseases."

Fly as model for studying the effect of maternal diet or obesity on offspring

Brookheart RT, Duncan JG. Drosophila melanogaster: An emerging model of transgenerational effects of maternal obesity. Mol Cell Endocrinol. 2016 Nov 5;435:20-8. PMID: 26687062; PMCID: PMC4903087.

From the abstract: "... Several studies in humans and rodents demonstrate a correlation between the risks of maternal overnutrition and factors such as epigenetics, mitochondrial dysfunction, insulin resistance, ER stress, and immune system disruption. At present, the molecular mechanisms connecting these factors to maternal obesity are unknown. This review focuses on the use of Drosophila melanogaster to study human metabolic diseases, including obesity, and its emerging use to elucidate the mechanisms of maternal overnutrition and the impact on offspring."

Fly data as confidence filter -- study related to alcohol dependence

Juraeva D, Treutlein J, Scholz H, Frank J, Degenhardt F, Cichon S, Ridinger M, Mattheisen M, Witt SH, Lang M, Sommer WH, Hoffmann P, Herms S, Wodarz N, Soyka M, Zill P, Maier W, Jünger E, Gaebel W, Dahmen N, Scherbaum N, Schmäl C, Steffens M, Lucae S, Ising M, Smolka MN, Zimmermann US, Müller-Myhsok B, Nöthen MM, Mann K, Kiefer F, Spanagel R, Brors B, Rietschel M. XRCC5 as a risk gene for alcohol dependence: evidence from a genome-wide gene-set-based analysis and follow-up studies in Drosophila and humans. Neuropsychopharmacology. 2015 Jan;40(2):361-71. PMID: 25035082; PMCID: PMC4443948.

From the abstract: "Genetic factors have as large role as environmental factors in the etiology of alcohol dependence (AD). Although genome-wide association studies (GWAS) enable systematic searches for loci not hitherto implicated in the etiology of AD, many true findings may be missed owing to correction for multiple testing. The aim of the present study was to circumvent this limitation by searching for biological system-level differences, and then following up these findings in humans and animals. ... In the present study, the functional role of XRCC5 in AD was further validated in animals and humans. Drosophila mutants with reduced function of Ku80-the homolog of mammalian XRCC5-due to RNAi silencing showed reduced sensitivity to ethanol. In humans with free access to intravenous ethanol self-administration in the laboratory, the maximum achieved blood alcohol concentration was influenced in an allele-dose-dependent manner by genetic variation in XRCC5. In conclusion, our convergent approach identified new candidates and generated independent evidence for the involvement of XRCC5 in alcohol dependence."

Fly data as confidence filter -- Drosophila in diabetes-related research

awasaki K, Yamada S, Ogata K, Saito Y, Takahama A, Yamada T, Matsumoto K, Kose H. Use of Drosophila as an evaluation method reveals imp as a candidate gene for type 2 diabetes in rat locus Niddm22. J Diabetes Res. 2015;2015:758564. PMID: 25821834; PMCID: PMC4363715.

From the abstract: "Type 2 diabetes (T2D) is one of the most common human diseases. QTL analysis of the diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats has identified numerous hyperglycemic loci. However, molecular characterization and/or gene identification largely remains to be elucidated ... Here we utilized Drosophila melanogaster as a secondary model organism for functional evaluation of the candidate gene. We demonstrate that the tissue specific knockdown of a homologue of igf2bp2 RNA binding protein leads to increased sugar levels similar to that found in the OLETF rat. ..."

Review highlights role of zebrafish and Drosophila studies in understanding muscular dystrophies

Plantié E, Migocka-Patrzałek M, Daczewska M, Jagla K. Model organisms in the fight against muscular dystrophy: lessons from drosophila and Zebrafish. Molecules. 2015 Apr 9;20(4):6237-53. PMID: 25859781.

From the abstract: "Muscular dystrophies (MD) are a heterogeneous group of genetic disorders that cause muscle weakness, abnormal contractions and muscle wasting, often leading to premature death. More than 30 types of MD have been described so far; those most thoroughly studied are Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1) and congenital MDs. ... To improve our knowledge of how MD-caused muscle defects arise and to find efficacious therapeutic treatments, different animal models have been generated and applied. Among these, simple non-mammalian Drosophila and zebrafish models have proved most useful. This review discusses how zebrafish and Drosophila MD have helped to identify genetic determinants of MDs and design innovative therapeutic strategies with a special focus on DMD, DM1 and congenital MDs."

Catching up on Drosophila papers related to neurodegenerative disease--research reports and a review

Alzheimer's disease

Liu QF, Lee JH, Kim YM, Lee S, Hong YK, Hwang S, Oh Y, Lee K, Yun HS, Lee IS, Jeon S, Chin YW, Koo BS, Cho KS. In Vivo Screening of Traditional Medicinal Plants for Neuroprotective Activity against Aβ42 Cytotoxicity by Using Drosophila Models of Alzheimer's Disease. Biol Pharm Bull. 2015;38(12):1891-901. PMID: 26458335.

Wang X, Perumalsamy H, Kwon HW, Na YE, Ahn YJ. Effects and possible mechanisms of action of acacetin on the behavior and eye morphology of Drosophila models of Alzheimer's disease. Sci Rep. 2015 Nov 4;5:16127. PMID: 26530776; PMCID: PMC4632086.

Kong Y, Wu J, Zhang D, Wan C, Yuan L. The Role of miR-124 in Drosophila Alzheimer's Disease Model by Targeting Delta in Notch Signaling Pathway. Curr Mol Med. 2015;15(10):980-9. PubMed PMID: 26592243.

Peng F, Zhao Y, Huang X, Chen C, Sun L, Zhuang L, Xue L. Loss of Polo ameliorates APP-induced Alzheimer's disease-like symptoms in Drosophila. Sci Rep. 2015 Nov 24;5:16816. PMID: 26597721; PMCID: PMC4657023.

Geng J, Xia L, Li W, Zhao C, Dou F. Cycloheximide Treatment Causes a ZVAD-Sensitive Protease-Dependent Cleavage of Human Tau in Drosophila Cells. J Alzheimers Dis. 2016;49(4):1161-8. PMID: 26599052; PMCID: PMC4927919.

Haddadi M, Nongthomba U, Jahromi SR, Ramesh SR. Transgenic Drosophila model to study apolipoprotein E4-induced neurodegeneration. Behav Brain Res. 2016 Mar 15;301:10-8. PMID: 26706888.

Wang X, Ma Y, Zhao Y, Chen Y, Hu Y, Chen C, Shao Y, Xue L. APLP1 promotes dFoxO-dependent cell death in Drosophila. Apoptosis. 2015 Jun;20(6):778-86. PMID: 25740230.

Lau HC, Lee IK, Ko PW, Lee HW, Huh JS, Cho WJ, Lim JO. Non-invasive screening for Alzheimer's disease by sensing salivary sugar using Drosophila cells expressing gustatory receptor (Gr5a) immobilized on an extended gate ion-sensitive field-effect transistor (EG-ISFET) biosensor. PLoS One. 2015 Feb 25;10(2):e0117810. PMID: 25714733; PMCID: PMC4340960.

Frenkel-Pinter M, Tal S, Scherzer-Attali R, Abu-Hussien M, Alyagor I, Eisenbaum T, Gazit E, Segal D. Naphthoquinone-Tryptophan Hybrid Inhibits Aggregation of the Tau-Derived Peptide PHF6 and Reduces Neurotoxicity. J Alzheimers Dis. 2016;51(1):165-78. PMID: 26836184.


Chai A, Pennetta G. Insights into ALS pathomechanisms: from flies to humans. Fly (Austin). 2015;9(2):91-8. PMID: 26594942; PMCID: PMC4826116. ---REVIEW

Cragnaz L, Klima R, De Conti L, Romano G, Feiguin F, Buratti E, Baralle M, Baralle FE. An age-related reduction of brain TBPH/TDP-43 levels precedes the onset of locomotion defects in a Drosophila ALS model. Neuroscience. 2015 Dec 17;311:415-21. PMID: 26518462.

Xia Q, Wang H, Hao Z, Fu C, Hu Q, Gao F, Ren H, Chen D, Han J, Ying Z, Wang G. TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. EMBO J. 2016 Jan 18;35(2):121-42. PMID: 26702100; PMCID: PMC4718457.

Romano M, Feiguin F, Buratti E. TBPH/TDP-43 modulates translation of Drosophila futsch mRNA through an UG-rich sequence within its 5'UTR. Brain Res. 2016 Sep 15;1647:50-6. doi: 10.1016/j.brainres.2016.02.022. PubMed PMID: 26902497.


Tran H, Almeida S, Moore J, Gendron TF, Chalasani U, Lu Y, Du X, Nickerson JA, Petrucelli L, Weng Z, Gao FB. Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS. Neuron. 2015 Sep 23;87(6):1207-14. PMID: 26402604; PMCID: PMC4589299.

Parkinson's disease

West RJ, Elliott CJ, Wade AR. Classification of Parkinson's Disease Genotypes in Drosophila Using Spatiotemporal Profiling of Vision. Sci Rep. 2015 Nov 24;5:16933. PMID: 26597171; PMCID: PMC4657034.

Gao F, Chen D, Si J, Hu Q, Qin Z, Fang M, Wang G. The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Hum Mol Genet. 2015 May 1;24(9):2528-38. PMID: 25612572.

Vos M, Verstreken P, Klein C. Stimulation of electron transport as potential novel therapy in Parkinson's disease with mitochondrial dysfunction. Biochem Soc Trans. 2015 Apr;43(2):275-9. PMID: 25849929.

Wiemerslage L, Lee D. Quantification of mitochondrial morphology in neurites of dopaminergic neurons using multiple parameters. J Neurosci Methods. 2016 Mar 15;262:56-65. PMID: 26777473; PMCID: PMC4775301. ---PROTOCOL

Langston RG, Rudenko IN, Cookson MR. The function of orthologues of the human Parkinson's disease gene LRRK2 across species: implications for disease modelling in preclinical research. Biochem J. 2016 Feb 1;473(3):221-32. PMID: 26811536.

Shiba-Fukushima K, Arano T, Matsumoto G, Inoshita T, Yoshida S, Ishihama Y, Ryu KY, Nukina N, Hattori N, Imai Y. Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering. PLoS Genet. 2014 Dec 4;10(12):e1004861. PMID: 25474007; PMCID: PMC4256268.


Poças GM, Branco-Santos J, Herrera F, Outeiro TF, Domingos PM. α-Synuclein modifies mutant huntingtin aggregation and neurotoxicity in Drosophila. Hum Mol Genet. 2015 Apr 1;24(7):1898-907. PMID: 25452431; PMCID: PMC4355023.

Stroedicke M, Bounab Y, Strempel N, Klockmeier K, Yigit S, Friedrich RP, Chaurasia G, Li S, Hesse F, Riechers SP, Russ J, Nicoletti C, Boeddrich A, Wiglenda T, Haenig C, Schnoegl S, Fournier D, Graham RK, Hayden MR, Sigrist S, Bates GP, Priller J, Andrade-Navarro MA, Futschik ME, Wanker EE. Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity. Genome Res. 2015 May;25(5):701-13. PMID: 25908449; PMCID: PMC4417118.

Spinal Cerebellar Ataxia

Blount JR, Tsou WL, Ristic G, Burr AA, Ouyang M, Galante H, Scaglione KM, Todi SV. Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23. Nat Commun. 2014 Aug 21;5:4638. PMID: 25144244; PMCID: PMC4237202.

Prion disease

Steinert JR. Prion protein as a mediator of synaptic transmission. Commun Integr Biol. 2015 Aug 14;8(4):e1063753. PMID: 26478992; PMCID: PMC4594542.

Catching up on Drosophila papers related to neurodegenerative disease--research reports and a review

Alzheimer's disease

Liu QF, Lee JH, Kim YM, Lee S, Hong YK, Hwang S, Oh Y, Lee K, Yun HS, Lee IS, Jeon S, Chin YW, Koo BS, Cho KS. In Vivo Screening of Traditional Medicinal Plants for Neuroprotective Activity against Aβ42 Cytotoxicity by Using Drosophila Models of Alzheimer's Disease. Biol Pharm Bull. 2015;38(12):1891-901. PMID: 26458335.

Wang X, Perumalsamy H, Kwon HW, Na YE, Ahn YJ. Effects and possible mechanisms of action of acacetin on the behavior and eye morphology of Drosophila models of Alzheimer's disease. Sci Rep. 2015 Nov 4;5:16127. PMID: 26530776; PMCID: PMC4632086.

Kong Y, Wu J, Zhang D, Wan C, Yuan L. The Role of miR-124 in Drosophila Alzheimer's Disease Model by Targeting Delta in Notch Signaling Pathway. Curr Mol Med. 2015;15(10):980-9. PubMed PMID: 26592243.

Peng F, Zhao Y, Huang X, Chen C, Sun L, Zhuang L, Xue L. Loss of Polo ameliorates APP-induced Alzheimer's disease-like symptoms in Drosophila. Sci Rep. 2015 Nov 24;5:16816. PMID: 26597721; PMCID: PMC4657023.

Geng J, Xia L, Li W, Zhao C, Dou F. Cycloheximide Treatment Causes a ZVAD-Sensitive Protease-Dependent Cleavage of Human Tau in Drosophila Cells. J Alzheimers Dis. 2016;49(4):1161-8. PMID: 26599052; PMCID: PMC4927919.

Haddadi M, Nongthomba U, Jahromi SR, Ramesh SR. Transgenic Drosophila model to study apolipoprotein E4-induced neurodegeneration. Behav Brain Res. 2016 Mar 15;301:10-8. PMID: 26706888.

Wang X, Ma Y, Zhao Y, Chen Y, Hu Y, Chen C, Shao Y, Xue L. APLP1 promotes dFoxO-dependent cell death in Drosophila. Apoptosis. 2015 Jun;20(6):778-86. PMID: 25740230.


Chai A, Pennetta G. Insights into ALS pathomechanisms: from flies to humans. Fly (Austin). 2015;9(2):91-8. PMID: 26594942; PMCID: PMC4826116. ---REVIEW

Cragnaz L, Klima R, De Conti L, Romano G, Feiguin F, Buratti E, Baralle M, Baralle FE. An age-related reduction of brain TBPH/TDP-43 levels precedes the onset of locomotion defects in a Drosophila ALS model. Neuroscience. 2015 Dec 17;311:415-21. PMID: 26518462.

Xia Q, Wang H, Hao Z, Fu C, Hu Q, Gao F, Ren H, Chen D, Han J, Ying Z, Wang G. TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. EMBO J. 2016 Jan 18;35(2):121-42. PMID: 26702100; PMCID: PMC4718457.


Tran H, Almeida S, Moore J, Gendron TF, Chalasani U, Lu Y, Du X, Nickerson JA, Petrucelli L, Weng Z, Gao FB. Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS. Neuron. 2015 Sep 23;87(6):1207-14. PMID: 26402604; PMCID: PMC4589299.

Parkinson's disease

West RJ, Elliott CJ, Wade AR. Classification of Parkinson's Disease Genotypes in Drosophila Using Spatiotemporal Profiling of Vision. Sci Rep. 2015 Nov 24;5:16933. PMID: 26597171; PMCID: PMC4657034.

Gao F, Chen D, Si J, Hu Q, Qin Z, Fang M, Wang G. The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Hum Mol Genet. 2015 May 1;24(9):2528-38. PMID: 25612572.

Vos M, Verstreken P, Klein C. Stimulation of electron transport as potential novel therapy in Parkinson's disease with mitochondrial dysfunction. Biochem Soc Trans. 2015 Apr;43(2):275-9. PMID: 25849929.

Prion disease

Steinert JR. Prion protein as a mediator of synaptic transmission. Commun Integr Biol. 2015 Aug 14;8(4):e1063753. PMID: 26478992; PMCID: PMC4594542.

Review in the journal Traffic on neuronal growth factor signaling -- relevance to ALS and hereditary spastic paraplegia

Deshpande M, Rodal AA. The Crossroads of Synaptic Growth Signaling, Membrane Traffic and Neurological Disease: Insights from Drosophila. Traffic. 2016 Feb;17(2):87-101. PMID: 26538429.

From the abstract: "... Neuronal growth factor signaling is highly dependent on membrane traffic... Here, we review recent findings from the Drosophila larval neuromuscular junction (NMJ) that illustrate how specific steps of intracellular traffic and inter-organelle interactions impinge on signaling ... These membrane trafficking and signaling pathways have been implicated in human motor neuron diseases including amyotrophic lateral sclerosis and hereditary spastic paraplegia, highlighting their importance for neuronal health and survival."

Effects on transcriptome of genotype and diet on metabolic phenotypes in Drosophila--relevance to understanding human obesity

Williams S, Dew-Budd K, Davis K, Anderson J, Bishop R, Freeman K, Davis D, Bray K, Perkins L, Hubickey J, Reed LK. Metabolomic and Gene Expression Profiles Exhibit Modular Genetic and Dietary Structure Linking Metabolic Syndrome Phenotypes in Drosophila. G3 (Bethesda). 2015 Nov 3;5(12):2817-29. PMID: 26530416; PMCID: PMC4683653.

From the abstract: "Genetic and environmental factors influence complex disease in humans, such as metabolic syndrome, and Drosophila melanogaster serves as an excellent model in which to test these factors experimentally. Here we explore the modularity of endophenotypes with an in-depth reanalysis of a previous study by Reed et al. (2014), where we raised 20 wild-type genetic lines of Drosophila larvae on four diets and measured gross phenotypes of body weight, total sugar, and total triglycerides, as well as the endophenotypes of metabolomic and whole-genome expression profiles. We then perform new gene expression experiments to test for conservation of phenotype-expression correlations across different diets and populations. We find that transcript levels correlated with gross phenotypes were enriched for puparial adhesion, metamorphosis, and central energy metabolism functions. ... This study demonstrates that variation for disease traits within a population is acquired through a multitude of physiological mechanisms, some of which transcend genetic and environmental influences, and others that are specific to an individual's genetic and environmental context."

Treatment of Drosophila model of DM1 with pentamidine reverses cellular and organismal phenotypes

Chakraborty M, Selma-Soriano E, Magny E, Couso JP, Pérez-Alonso M, Charlet-Berguerand N, Artero R, Llamusi B. Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction. Dis Model Mech. 2015 Dec;8(12):1569-78. PMID: 26515653; PMCID: PMC4728315.

From the abstract: "Up to 80% of individuals with myotonic dystrophy type 1 (DM1) will develop cardiac abnormalities at some point during the progression of their disease, the most common of which is heart blockage ... Such blockage is characterized by conduction defects and supraventricular and ventricular tachycardia, and carries a high risk of sudden cardiac death. ... Here, we describe the characterization of the heart phenotype in a Drosophila model expressing pure expanded CUG repeats under the control of the cardiomyocyte-specific driver GMH5-Gal4. ... As a proof of concept that the fly heart model can be used for in vivo testing of promising therapeutic compounds, we fed flies with pentamidine, a compound previously described to improve DM1 phenotypes. Pentamidine not only released Muscleblind from the CUG RNA repeats and reduced ribonuclear formation in the Drosophila heart, but also rescued heart arrhythmicity and contractility, and improved fly survival in animals expressing 250 CUG repeats."

Exploring a linke between Parkinson's and epilepsy through study of the Drosophila mutant easily shocked

Witt SN. Lipid disequilibrium in biological membranes, a possible pathway to neurodegeneration. Commun Integr Biol. 2015 Jan 8;7(6):e993266. PMID: 26480301; PMCID: PMC4594524.

From the abstract: "... Here we highlight a Drosophila mutant called easily shocked-thought to be a model of epilepsy-that cannot use ethanolamine to synthesize PE. ... We propose that disruptions in lipid homeostasis (synthesis and degradation) may be responsible for some cases of PD and epilepsy."

Monday, December 12, 2016

Testing traditional medical treatments in a fly model of Alzheimer's disease

Liu QF, Lee JH, Kim YM, Lee S, Hong YK, Hwang S, Oh Y, Lee K, Yun HS, Lee IS, Jeon S, Chin YW, Koo BS, Cho KS. In Vivo Screening of Traditional Medicinal Plants for Neuroprotective Activity against Aβ42 Cytotoxicity by Using Drosophila Models of Alzheimer's Disease. Biol Pharm Bull. 2015;38(12):1891-901. PMID: 26458335.

From the abstract: "Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive neuronal loss with amyloid β-peptide (Aβ) plaques. Despite several drugs currently used to treat AD, their beneficial effects on AD progress remains under debate. Here, we established a rapid in vivo screening system using Drosophila AD models to assess the neuroprotective activities of medicinal plants that have been used in traditional Chinese medicine. Among 23 medicinal plants tested, the extracts from five plants, Coriandrum sativum, Nardostachys jatamansi, Polygonum multiflorum (P. multiflorum), Rehmannia glutinosa, and Sorbus commixta (S. commixta), showed protective effects against the Aβ42 neurotoxicity. We further characterized the neuroprotective activity of ethanol extracts from P. multiflorum and S. commixta. ..."

Review highlights what's right about the fly for neurodegenerative disease-related research

McGurk L, Berson A, Bonini NM. Drosophila as an In Vivo Model for Human Neurodegenerative Disease. Genetics. 2015 Oct;201(2):377-402. PMID: 26447127; PMCID: PMC4596656.

From the abstract: "With the increase in the ageing population, neurodegenerative disease is devastating to families and poses a huge burden on society. ... The fruit fly, Drosophila melanogaster, has been proven tremendously valuable as a model organism, enabling many major discoveries in neuroscientific disease research. The plethora of genetic tools available in Drosophila allows for exquisite targeted manipulation of the genome. Due to its relatively short lifespan, complex questions of brain function can be addressed more rapidly than in other model organisms, such as the mouse. Here we discuss features of the fly as a model for human neurodegenerative disease. ... we underscore strengths of the fly in providing understanding into mechanisms and pathways, as a foundation for translational and therapeutic research."

Fly study provides link between GOLPH3 protein function and cancer-related cell functions

Sechi S, Frappaolo A, Belloni G, Giansanti MG. The roles of the oncoprotein GOLPH3 in contractile ring assembly and membrane trafficking during cytokinesis. Biochem Soc Trans. 2015 Feb;43(1):117-21. PMID: 25619256.

From the abstract: "... the molecular mechanisms involved in coupling the cytoskeleton dynamics with vesicle trafficking during cytokinesis are poorly understood. The highly conserved Golgi phosphoprotein 3 (GOLPH3), functions as a phosphatidylinositol 4-phosphate (PI4P) effector at the Golgi. Recent studies have suggested that GOLPH3 is up-regulated in several cancers and is associated with poor prognosis and more aggressive tumours. In Drosophila melanogaster, GOLPH3 localizes at the cleavage furrow of dividing cells, is required for successful cytokinesis and acts as a key molecule in coupling phosphoinositide (PI) signalling with actomyosin ring dynamics. Because cytokinesis failures have been linked with pre-malignant disease and cancer, the novel connection between GOLPH3 and cytokinesis imposes new fields of investigation in cancer biology and therapy."

Drosophila model used in study related to myotonic dystrophy type 1

Wong CH, Nguyen L, Peh J, Luu LM, Sanchez JS, Richardson SL, Tuccinardi T, Tsoi H, Chan WY, Chan HY, Baranger AM, Hergenrother PJ, Zimmerman SC. Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor. J Am Chem Soc. 2014 Apr 30;136(17):6355-61. PMID: 24702247; PMCID: PMC4015652.

From the abstract: "A working hypothesis for the pathogenesis of myotonic dystrophy type 1 (DM1) involves the aberrant sequestration of an alternative splicing regulator, MBNL1, by expanded CUG repeats, r(CUG)(exp). It has been suggested that a reversal of the myotonia and potentially other symptoms of the DM1 disease can be achieved by inhibiting the toxic MBNL1-r(CUG)(exp) interaction. Using rational design, we discovered an RNA-groove binding inhibitor (ligand 3) that contains two triaminotriazine units connected by a bisamidinium linker. ... Importantly, suppression of r(CUG)(exp) RNA-induced toxicity in a DM1 Drosophila model was observed after treatment with ligand 3. These results suggest ligand 3 as a lead for the treatment of DM1."

Using the fly to investigate what links xeroderma pigmentosum to cancer risk

Stettler K, Li X, Sandrock B, Braga-Lagache S, Heller M, Dümbgen L, Suter B. A Drosophila XPD model links cell cycle coordination with neuro-development and suggests links to cancer. Dis Model Mech. 2015 Jan;8(1):81-91. PMID: 25431422; PMCID: PMC4283652.

From the abstract: "XPD functions in transcription, DNA repair and in cell cycle control. Mutations in human XPD (also known as ERCC2) mainly cause three clinical phenotypes: xeroderma pigmentosum (XP), Cockayne syndrome (XP/CS) and trichothiodystrophy (TTD), and only XP patients have a high predisposition to developing cancer. Hence, we developed a fly model to obtain novel insights into the defects caused by individual hypomorphic alleles identified in human XP-D patients. This model revealed that the mutations that displayed the greatest in vivo UV sensitivity in Drosophila did not correlate with those that led to tumor formation in humans. Immunoprecipitations followed by targeted quantitative MS/MS analysis showed how different xpd mutations affected the formation or stability of different transcription factor IIH (TFIIH) subcomplexes. The XP mutants most clearly linked to high cancer risk, Xpd R683W and R601L, showed a reduced interaction with the core TFIIH and also an abnormal interaction with the Cdk-activating kinase (CAK) complex. ..."

New fly model of myotonic dystrophy type 2

Yu Z, Goodman LD, Shieh SY, Min M, Teng X, Zhu Y, Bonini NM. A fly model for the CCUG-repeat expansion of myotonic dystrophy type 2 reveals a novel interaction with MBNL1. Hum Mol Genet. 2015 Feb 15;24(4):954-62. PMID: 25305073.

From the abstract: "Expanded non-coding RNA repeats of CUG and CCUG are the underlying genetic causes for myotonic dystrophy type 1 (DM1) and type 2 (DM2), respectively. A gain-of-function of these pathogenic repeat expansions is mediated at least in part by their abnormal interactions with RNA-binding proteins such as MBNL1 and resultant loss of activity of these proteins. To study pathogenic mechanisms of CCUG-repeat expansions in an animal model, we created a fly model of DM2 that expresses pure, uninterrupted CCUG-repeat expansions ranging from 16 to 720 repeats in length. We show that this fly model for DM2 recapitulates key features of human DM2 including RNA repeat-induced toxicity, ribonuclear foci formation and changes in alternative splicing. ... Our results suggest a novel mechanism for interaction between the pathogenic RNA repeat expansions of myotonic dystrophy and MBNL1."

Fly as whole-animal petri dish: exploring pathogenesis related to Huntington's disease

Barbaro BA, Lukacsovich T, Agrawal N, Burke J, Bornemann DJ, Purcell JM, Worthge SA, Caricasole A, Weiss A, Song W, Morozova OA, Colby DW, Marsh JL. Comparative study of naturally occurring huntingtin fragments in Drosophila points to exon 1 as the most pathogenic species in Huntington's disease. Hum Mol Genet. 2015 Feb 15;24(4):913-25. PMID: 25305076; PMCID: PMC4834878.

From the abstract: "Although Huntington's disease is caused by the expansion of a CAG triplet repeat within the context of the 3144-amino acid huntingtin protein (HTT), studies reveal that N-terminal fragments of HTT containing the expanded PolyQ region can be produced by proteolytic processing and/or aberrant splicing. N-terminal HTT fragments are also prevalent in postmortem tissue, and expression of some of these fragments in model organisms can cause pathology. This has led to the hypothesis that N-terminal peptides may be critical modulators of disease pathology, raising the possibility that targeting aberrant splicing or proteolytic processing may present attractive therapeutic targets. ... We have used Drosophila as a model system to determine the relative toxicities of different naturally occurring huntingtin fragments in a system in which genetic background, transgene expression levels and post-translational proteolytic processing can be controlled. ... If this proves correct, efforts to specifically reduce the levels of exon 1 peptides or to target toxicity-influencing post-translational modifications that occur with the exon 1 context are likely to have the greatest impact on pathology."

Video methods: modeling TBI in the fly

Katzenberger RJ, Loewen CA, Bockstruck RT, Woods MA, Ganetzky B, Wassarman DA. A Method to Inflict Closed Head Traumatic Brain Injury in Drosophila. J Vis Exp. 2015 Jun 30;(100):e52905. doi: 10.3791/52905. Erratum in: J Vis Exp. 2015;(101):e5744. Ganetky, Barry [corrected to Ganetzky, Barry]. PMID: 26168076.

From the abstract: "Traumatic brain injury (TBI) affects millions of people each year, causing impairment of physical, cognitive, and behavioral functions and death. Studies using Drosophila have contributed important breakthroughs in understanding neurological processes. Thus, with the goal of understanding the cellular and molecular basis of TBI pathologies in humans, we developed the High Impact Trauma (HIT) device to inflict closed head TBI in flies. ... the HIT device can be used to perform large-scale genetic screens to understand the genetic basis of TBI pathologies."

Results of fly study shed new light on cellular and organismal functions of ALS-related proteins

Coyne AN, Yamada SB, Siddegowda BB, Estes PS, Zaepfel BL, Johannesmeyer JS, Lockwood DB, Pham LT, Hart MP, Cassel JA, Freibaum B, Boehringer AV, Taylor JP, Reitz AB, Gitler AD, Zarnescu DC. Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation. Hum Mol Genet. 2015 Dec 15;24(24):6886-98. PMID: 26385636; PMCID: PMC5007633.

From the abstract:
"RNA dysregulation is a newly recognized disease mechanism in amyotrophic lateral sclerosis (ALS). Here we identify Drosophila fragile X mental retardation protein (dFMRP) as a robust genetic modifier of TDP-43-dependent toxicity in a Drosophila model of ALS. We find that dFMRP overexpression (dFMRP OE) mitigates TDP-43 dependent locomotor defects and reduced lifespan in Drosophila. TDP-43 and FMRP form a complex in flies and human cells. ... Our data suggest a model whereby dFMRP is neuroprotective by remodeling TDP-43 containing RNA granules, reducing aggregation and restoring the translation of specific mRNAs in motor neurons."

Tuesday, November 22, 2016

Review of involvement in disease of human orthologs of the Drosophila gene crumbs

Slavotinek AM. The Family of Crumbs Genes and Human Disease. Mol Syndromol. 2016 Oct;7(5):274-281. PMID: 27867342.

From the abstract: "The family of vertebrate Crumbs proteins, homologous to Drosophila Crumbs (Crb), share large extracellular domains with epidermal growth factor-like repeats and laminin-globular domains, a single transmembrane domain, and a short intracellular C-terminus containing a single membrane proximal 4.1/ezrin/radixin/moesin-binding domain and PSD-95/Discs large/ZO-1-binding motifs. There are 3 Crb genes in humans ... Bilallelic loss-of-function mutations in CRB1 cause visual impairment, with Leber's congenital amaurosis and retinitis pigmentosa, whereas CRB2 mutations are associated with raised maternal serum and amniotic fluid alpha feto-protein levels, ventriculomegaly/hydrocephalus, and renal disease, ranging from focal segmental glomerulosclerosis to congenital Finnish nephrosis. ... In this review, we summarize the phenotypic findings associated with deleterious sequence variants in CRB1 and CRB2. We discuss the mutational spectrum, animal models of loss of function for both genes and speculate on the likely mechanisms of disease."

Thursday, October 27, 2016

Do p53 mutations result in 'transposon-opathies'?

The interesting argument regarding p53, transposons, and cancer that is presented in this review draws in part from studies done in flies.

Wylie A, Jones AE, Abrams JM. p53 in the game of transposons. Bioessays. 2016 Nov;38(11):1111-1116. PMID: 27644006.

From the abstract: "Throughout the animal kingdom, p53 genes function to restrain mobile elements and recent observations indicate that transposons become derepressed in human cancers. ..."

Wednesday, October 26, 2016

Review of animal models of SMA

Edens BM, Ajroud-Driss S, Ma L, Ma YC. Molecular mechanisms and animal models of spinal muscular atrophy. Biochim Biophys Acta. 2015 Apr;1852(4):685-92. PMID: 25088406.

Fly, mouse, and human cell models of Duchenne muscular dystrophy used to evaluate exon skipping as a potential therapeutic strategy

Gao QQ, Wyatt E, Goldstein JA, LoPresti P, Castillo LM, Gazda A, Petrossian N, Earley JU, Hadhazy M, Barefield DY, Demonbreun AR, Bönnemann C, Wolf M, McNally EM. Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping. J Clin Invest. 2015 Nov 2;125(11):4186-95. PMID: 26457733; PMCID: PMC4639981.

From the abstract: "Exon skipping uses antisense oligonucleotides as a treatment for genetic diseases. ... Exon skipping is currently being tested in humans with dystrophin gene mutations who have Duchenne muscular dystrophy. ... We generated an internally truncated γ-sarcoglycan protein that we have termed Mini-Gamma by deleting a large portion of the extracellular domain. Mini-Gamma provided functional and pathological benefits to correct the loss of γ-sarcoglycan in a Drosophila model, in heterologous cell expression studies, and in transgenic mice lacking γ-sarcoglycan. We generated a cellular model of human muscle disease and showed that multiple exon skipping could be induced in RNA that encodes a mutant human γ-sarcoglycan. Since Mini-Gamma represents removal of 4 of the 7 coding exons in γ-sarcoglycan, this approach provides a viable strategy to treat the majority of patients with γ-sarcoglycan gene mutations."

Fly model of Alzheimer's disease tested with potentially bioactive viridins extracted from endolichenic fungi

Zhao Q, Chen GD, Feng XL, Yu Y, He RR, Li XX, Huang Y, Zhou WX, Guo LD, Zheng YZ, Yao XS, Gao H. Nodulisporiviridins A-H, Bioactive Viridins from Nodulisporium sp. J Nat Prod. 2015 Jun 26;78(6):1221-30. PMID: 25978520.

From the abstract: "Eight new viridins, nodulisporiviridins A-H (1-8), were isolated from the extract of an endolichenic fungal strain Nodulisporium sp. (No. 65-17-2-1) that was fermented with potato-dextrose broth. ... The short-term memory assay on an Aβ transgenic drosophila model of Alzheimer's disease showed that all eight compounds improved the short-term memory capacity, with potencies close to that of the positive control (memantine)."

Fly eye study related to Alzheimer's disease

Cutler T, Sarkar A, Moran M, Steffensmeier A, Puli OR, Mancini G, Tare M, Gogia N, Singh A. Drosophila Eye Model to Study Neuroprotective Role of CREB Binding Protein (CBP) in Alzheimer's Disease. PLoS One. 2015 Sep 14;10(9):e0137691. PMID: 26367392; PMCID: PMC4569556.

Characterization of sleep in a fly model of epilepsy

Petruccelli E, Lansdon P, Kitamoto T. Exaggerated Nighttime Sleep and Defective Sleep Homeostasis in a Drosophila Knock-In Model of Human Epilepsy. PLoS One. 2015 Sep 11;10(9):e0137758. PMID: 26361221; PMCID: PMC4567262.

From the abstract: "Despite an established link between epilepsy and sleep behavior, it remains unclear how specific epileptogenic mutations affect sleep and subsequently influence seizure susceptibility. ... Here, we show that at room temperature the GEFS+ mutation dominantly modifies sleep, with mutants exhibiting rapid sleep onset at dusk and increased nighttime sleep as compared to controls.  ... Additionally, analyses under other light conditions suggested that the GEFS+ mutation led to reduced buffering of behavioral responses to light on and off stimuli, which contributed to characteristic GEFS+ sleep phenotypes. ... Our study has revealed the sleep architecture of a Drosophila VGSC mutant that harbors a human GEFS+ mutation, and provided unique insight into the relationship between sleep and epilepsy."

Green-glowing flies used in study relevant to Huntington's disease

Babcock DT, Ganetzky B. Transcellular spreading of huntingtin aggregates in the Drosophila brain. Proc Natl Acad Sci U S A. 2015 Sep 29;112(39):E5427-33. PMID: 26351672; PMCID: PMC4593132.

From the abstract: "A key feature of many neurodegenerative diseases is the accumulation and subsequent aggregation of misfolded proteins. Recent studies have highlighted the transcellular propagation of protein aggregates in several major neurodegenerative diseases, although the precise mechanisms underlying this spreading and how it relates to disease pathology remain unclear. Here we use a polyglutamine-expanded form of human huntingtin (Htt) with a fluorescent tag to monitor the spreading of aggregates in the Drosophila brain in a model of Huntington's disease. ... We show that Htt aggregates cause non-cell-autonomous pathology ..."

Uncovering cellular mechanisms relevant to Parkinson's Disease

Dodson MW, Leung LK, Lone M, Lizzio MA, Guo M. Novel ethyl methanesulfonate (EMS)-induced null alleles of the Drosophila homolog of LRRK2 reveal a crucial role in endolysosomal functions and autophagy in vivo. Dis Model Mech. 2014 Dec;7(12):1351-63. PMID: 25288684; PMCID: PMC4257004.

Zhou ZD, Xie SP, Sathiyamoorthy S, Saw WT, Sing TY, Ng SH, Chua HP, Tang AM, Shaffra F, Li Z, Wang H, Ho PG, Lai MK, Angeles DC, Lim TM, Tan EK. F-box protein 7 mutations promote protein aggregation in mitochondria and inhibit mitophagy. Hum Mol Genet. 2015 Nov 15;24(22):6314-30. PMID: 26310625.

Kong Y, Liang X, Liu L, Zhang D, Wan C, Gan Z, Yuan L. High Throughput Sequencing Identifies MicroRNAs Mediating α-Synuclein Toxicity by Targeting Neuroactive-Ligand Receptor Interaction Pathway in Early Stage of Drosophila Parkinson's Disease Model. PLoS One. 2015 Sep 11;10(9):e0137432. PMID: 26361355; PMCID: PMC4567341.

Gehrke S, Wu Z, Klinkenberg M, Sun Y, Auburger G, Guo S, Lu B. PINK1 and Parkin control localized translation of respiratory chain component mRNAs on mitochondria outer membrane. Cell Metab. 2015 Jan 6;21(1):95-108. PMID: 25565208; PMCID: PMC4455944.

Shmueli MD, Schnaider L, Herzog G, Gazit E, Segal D. Computational and experimental characterization of dVHL establish a Drosophila model of VHL syndrome. PLoS One. 2014 Oct 13;9(10):e109864. PMID: 25310726; PMCID: PMC4195687.

Dubos A, Castells-Nobau A, Meziane H, Oortveld MA, Houbaert X, Iacono G, Martin C, Mittelhaeuser C, Lalanne V, Kramer JM, Bhukel A, Quentin C, Slabbert J, Verstreken P, Sigrist SJ, Messaddeq N, Birling MC, Selloum M, Stunnenberg HG, Humeau Y, Schenck A, Herault Y. Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration. Hum Mol Genet. 2015 Dec 1;24(23):6736-55. PMID: 26376863; PMCID: PMC4634377.

Arsenijevic Y. Cell Cycle Proteins and Retinal Degeneration: Evidences of New Potential Therapeutic Targets. Adv Exp Med Biol. 2016;854:371-7. PMID: 26427434.

Angelova PR, Agrawalla BK, Elustondo PA, Gordon J, Shiba T, Abramov AY, Chang YT, Pavlov EV. In situ investigation of mammalian inorganic polyphosphate localization using novel selective fluorescent probes JC-D7 and JC-D8. ACS Chem Biol. 2014 Sep 19;9(9):2101-10. PMID: 25007079.

van der Merwe C, Jalali Sefid Dashti Z, Christoffels A, Loos B, Bardien S. Evidence for a common biological pathway linking three Parkinson's disease-causing genes: parkin, PINK1 and DJ-1. Eur J Neurosci. 2015 May;41(9):1113-25. PMID: 25761903.

Characterization of a fly model of glassic galactosemia

Jumbo-Lucioni P, Parkinson W, Broadie K. Overelaborated synaptic architecture and reduced synaptomatrix glycosylation in a Drosophila classic galactosemia disease model. Dis Model Mech. 2014 Dec;7(12):1365-78. PMID: 25326312; PMCID: PMC4257005.

From the abstract: "Classic galactosemia (CG) is an autosomal recessive disorder resulting from loss of galactose-1-phosphate uridyltransferase (GALT), which catalyzes conversion of galactose-1-phosphate and uridine diphosphate (UDP)-glucose to glucose-1-phosphate and UDP-galactose, immediately upstream of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine synthesis. These four UDP-sugars are essential donors for driving the synthesis of glycoproteins and glycolipids, which heavily decorate cell surfaces and extracellular spaces. In addition to acute, potentially lethal neonatal symptoms, maturing individuals with CG develop striking neurodevelopmental, motor and cognitive impairments. Previous studies suggest that neurological symptoms are associated with glycosylation defects, with CG recently being described as a congenital disorder of glycosylation (CDG), showing defects in both N- and O-linked glycans. Here, we characterize behavioral traits, synaptic development and glycosylated synaptomatrix formation in a GALT-deficient Drosophila disease model. ... These results reveal synaptomatrix glycosylation losses, altered trans-synaptic signaling pathway components, defective synaptogenesis and impaired coordinated movement in a CG neurological disease model."

Fly study uncovers new information regarding the cellular role of the ALS related gene TDP-43

Miskiewicz K, Jose LE, Yeshaw WM, Valadas JS, Swerts J, Munck S, Feiguin F, Dermaut B, Verstreken P. HDAC6 is a Bruchpilot deacetylase that facilitates neurotransmitter release. Cell Rep. 2014 Jul 10;8(1):94-102. PMID: 24981865.

From the abstract: "... reduced levels of HDAC6 or increased levels of ELP3, a Bruchpilot acetyltransferase, rescue the presynaptic density defects in TDP-43-expressing flies as well as the decreased adult locomotion ..."

Report of a "true ortholog" in flies of the human Charcot-Marie-Tooth disease-related gene GDAP1

López Del Amo V, Seco-Cervera M, García-Giménez JL, Whitworth AJ, Pallardó FV, Galindo MI. Mitochondrial defects and neuromuscular degeneration caused by altered expression of Drosophila Gdap1: implications for the Charcot-Marie-Tooth neuropathy. Hum Mol Genet. 2015 Jan 1;24(1):21-36. PMID: 25122658.

From the abstract: "One of the genes involved in Charcot-Marie-Tooth (CMT) disease, an inherited peripheral neuropathy, is GDAP1. In this work, we show that there is a true ortholog of this gene in Drosophila, which we have named Gdap1. By up- and down-regulation of Gdap1 in a tissue-specific manner, we show that altering its levels of expression produces changes in mitochondrial size, morphology and distribution, and neuronal and muscular degeneration. ... Our results contribute to a better understanding of the role of mitochondria in CMT disease and pave the way to generate clinically relevant disease models to study the relationship between mitochondrial dynamics and peripheral neurodegeneration."

Can we outrun aging? Fly study of impact of fatiguing exercise on aging

Zheng L, Feng Y, Wen DT, Wang H, Wu XS. Fatiguing exercise initiated later in life reduces incidence of fibrillation and improves sleep quality in Drosophila. Age (Dordr). 2015 Aug;37(4):9816. PMID: 26206392; PMCID: PMC4512962.

From the abstract: "As the human body ages, the risk of heart disease and stroke greatly increases. While there is evidence that lifelong exercise is beneficial to the heart's health, the effects of beginning exercise later in life remain unclear. This study aimed to investigate whether exercise training started later in life is beneficial to cardiac aging in Drosophila. ... We found that 2.0 and 2.5 h of exercise caused exercise-induced fatigue, and fatiguing exercise is beneficial for cardiac and healthy aging overall. This study provides a basis for further study in humans on the impact of beginning an exercise regimen later in life on cardiac health."

Fly studies contribute to study focused on centronuclear myopathy

Chin YH, Lee A, Kan HW, Laiman J, Chuang MC, Hsieh ST, Liu YW. Dynamin-2 mutations associated with centronuclear myopathy are hypermorphic and lead to T-tubule fragmentation. Hum Mol Genet. 2015 Oct 1;24(19):5542-54. PMID: 26199319.

From the abstract: "Skeletal muscle requires adequate membrane trafficking and remodeling to maintain its normal structure and functions. Consequently, many human myopathies are caused by mutations in membrane trafficking machinery. The large GTPase dynamin-2 (Dyn2) is best known for catalyzing membrane fission during clathrin-mediated endocytosis (CME), which is critical for cell signaling and survival. Despite its ubiquitous expression, mutations of Dyn2 are associated with two tissue-specific congenital disorders: centronuclear myopathy (CNM) and Charcot-Marie-Tooth (CMT) neuropathy. Several disease models for CNM-Dyn2 have been established ... . ... we found that the expression of CNM-Dyn2 mutants does not impair CME in myoblast, but leads to T-tubule fragmentation in both C2C12-derived myotubes and Drosophila body wall muscle. Our results demonstrate that CNM-Dyn2 mutants are gain-of-function mutations, and their primary effect in muscle is T-tubule disorganization, which explains the susceptibility of muscle to Dyn2 hyperactivity."

Drosophila studies contribute to research on possible links between the metal copper and schizophrenia

Gokhale A, Vrailas-Mortimer A, Larimore J, Comstra HS, Zlatic SA, Werner E, Manvich DF, Iuvone PM, Weinshenker D, Faundez V. Neuronal copper homeostasis susceptibility by genetic defects in dysbindin, a schizophrenia susceptibility factor. Hum Mol Genet. 2015 Oct 1;24(19):5512-23. PMID: 26199316; PMCID: PMC4572075.

From the abstract: "Environmental factors and susceptible genomes interact to determine the risk of neurodevelopmental disorders. ... Here we focus on the schizophrenia susceptibility gene DTNBP1 and its product dysbindin, a subunit of the BLOC-1 complex, and describe a neuronal pathway modulating copper metabolism via ATP7A. ... Dysbindin/BLOC-1 loss-of-function alleles do not affect cell and tissue copper content, yet they alter the susceptibility to toxic copper challenges in both mammalian cells and Drosophila. Our results demonstrate that perturbations downstream of the schizophrenia susceptibility gene DTNBP1 confer susceptibility to copper, a metal that in excess is a neurotoxin and whose depletion constitutes a micronutrient deficiency."

Modeling neurodegenerative disease

Lepesant JA. The promises of neurodegenerative disease modeling. C R Biol. 2015 Aug-Sep;338(8-9):584-92. PMID: 26210484.

From the abstract: "The rise in the prevalence of neurodegenerative diseases parallels the rapid increase in human lifespan. Despite intensive research, the molecular and cellular mechanisms underlying the onset and progression of these devastating diseases with age are still poorly understood. ... This review will focus on the advantages offered by the genetic tools available in Drosophila for combining powerful strategies in order to tackle the causative factors of these complex pathologies and help to elaborate efficient drugs to treat them."

Thursday, October 6, 2016

Preprint describes new fly model of Saposin deficiency

A Saposin deficiency model in Drosophila: lysosomal storage, progressive neurodegeneration, sensory physiological decline and defective calcium homeostasis

J Hindle, Sarita Hebbar, Dominik Schwudke, Christopher J Elliott, Sean T Sweeney

From the abstract: "Saposin deficiency is a childhood neurodegenerative lysosomal storage disorder (LSD) that can cause premature death within three months of life. Saposins are activator proteins that promote the function of lysosomal hydrolases in the degradation of sphingolipids. There are four saposin proteins in humans, which are encoded by the prosaposin gene. Mutations causing an absence of individual saposins or the whole prosaposin gene lead to distinct LSDs due to the storage of different classes of sphingolipids. The pathological events leading to neuronal dysfunction induced by lysosomal storage of sphingolipids are as yet poorly defined. We have generated and characterised a Drosophila model of saposin deficiency that shows striking similarities to the human diseases. ..."

Thursday, September 15, 2016

Fly study points to importance and approaches for precision/personalized medicine in Ret fusion-associated cancers

Levinson S, Cagan RL. Drosophila Cancer Models Identify Functional Differences between Ret Fusions. Cell Rep. 2016 Sep 13;16(11):3052-3061. PMID: 27626672.

Abstract: "We generated and compared Drosophila models of RET fusions CCDC6-RET and NCOA4-RET. Both RET fusions directed cells to migrate, delaminate, and undergo EMT, and both resulted in lethality when broadly expressed. In all phenotypes examined, NCOA4-RET was more severe than CCDC6-RET, mirroring their effects on patients. A functional screen against the Drosophila kinome and a library of cancer drugs found that CCDC6-RET and NCOA4-RET acted through different signaling networks and displayed distinct drug sensitivities. Combining data from the kinome and drug screens identified the WEE1 inhibitor AZD1775 plus the multi-kinase inhibitor sorafenib as a synergistic drug combination that is specific for NCOA4-RET. Our work emphasizes the importance of identifying and tailoring a patient's treatment to their specific RET fusion isoform and identifies a multi-targeted therapy that may prove effective against tumors containing the NCOA4-RET fusion."

Monday, September 12, 2016

Experiments in Drosophila contribute to characterization of links between kidney disease and salt stress

Mahajan A, Rodan AR, Le TH, Gaulton KJ, Haessler J, Stilp AM, Kamatani Y, Zhu G, Sofer T, Puri S, Schellinger JN, Chu PL, Cechova S, van Zuydam N; SUMMIT Consortium; BioBank Japan Project, Arnlov J, Flessner MF, Giedraitis V, Heath AC, Kubo M, Larsson A, Lindgren CM, Madden PA, Montgomery GW, Papanicolaou GJ, Reiner AP, Sundström J, Thornton TA, Lind L, Ingelsson E, Cai J, Martin NG, Kooperberg C, Matsuda K, Whitfield JB, Okada Y, Laurie CC, Morris AP, Franceschini N. Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity. Am J Hum Genet. 2016 Sep 1;99(3):636-46. PMID: 27588450.

From the abstract: "We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function ... We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci ... Loss-of-function mutations in ancestral orthologs of both [NFATC1 and RGS14] genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. ... Our study ... suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans."

Friday, August 19, 2016

Thursday, July 28, 2016

Uncovering the cellular function of Torsins -- relevance to DYT1 dystonia

Grillet M, Dominguez Gonzalez B, Sicart A, Pöttler M, Cascalho A, Billion K, Hernandez Diaz S, Swerts J, Naismith TV, Gounko NV, Verstreken P, Hanson PI, Goodchild RE. Torsins Are Essential Regulators of Cellular Lipid Metabolism. Dev Cell. 2016 Jul 14. PMID: 27453503.

From the abstract: "Torsins are developmentally essential AAA+ proteins, and mutation of human torsinA causes the neurological disease DYT1 dystonia. They localize in the ER membranes, but their cellular function remains unclear. We now show that dTorsin is required in Drosophila adipose tissue, where it suppresses triglyceride levels, promotes cell growth, and elevates membrane lipid content. We also see that human torsinA at the inner nuclear membrane is associated with membrane expansion and elevated cellular lipid content. ... These findings identify that torsins are essential regulators of cellular lipid metabolism and implicate disturbed lipid biology in childhood-onset DYT1 dystonia."

Monday, July 25, 2016

Exploring the relationship of metals to Friedreich's ataxia

Soriano S, Calap-Quintana P, Llorens JV, Al-Ramahi I, Gutiérrez L, Martínez-Sebastián MJ, Botas J, Moltó MD. Metal Homeostasis Regulators Suppress FRDA Phenotypes in a Drosophila Model of the Disease. PLoS One. 2016 Jul 19;11(7):e0159209. PMID: 27433942.

From the abstract: "Friedreich's ataxia (FRDA), the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance. ... we identified that genes implicated in iron, zinc and copper transport and metal detoxification can restore frataxin deficiency-induced phenotypes. Taken together, these results demonstrate that the metal dysregulation in FRDA includes other metals besides iron, therefore providing a new set of potential therapeutic targets."

Monday, July 18, 2016

If it sickens flies, do I want it in me? Using Drosophila to assess toxicity of plant extracts

Júnior FE, Macedo GE, Zemolin AP, Silva GF, Cruz LC, Boligon AA, de Menezes IR, Franco JL, Posser T. Oxidant effects and toxicity of Croton campestris in Drosophila melanogaster. Pharm Biol. 2016 Jul 14:1-10. PMID: 27417881.

From the abstract:  "... Croton campestris ... is a species native to Northeast Brazil used by traditional communities for the treatment of a variety of health problems. ... The potential toxicity of the hydroalcoholic extract of C. campestris leaves on Drosophila melanogaster ... were analysed in this study. ... Our data show important toxicological effects of C. campestris leading to increased mortality and impaired locomotor performance accompanied by induction of cell stress markers in flies. The study draws attention to the indiscriminate use of plant extracts."

Wednesday, June 15, 2016

Drosophila as a model for cancer drug development (review article)

Yadav AK, Srikrishna S, Gupta SC. Cancer Drug Development Using Drosophila as an in vivo Tool: From Bedside to Bench and Back. Trends Pharmacol Sci. 2016 Jun 10. pii: S0165-6147(16)30053-0. PMID: 27298020.

From the abstract: "The fruit fly Drosophila melanogaster has been used for modeling cancer and as an in vivo tool for the validation and/or development of cancer therapeutics. The impetus for the use of Drosophila in cancer research stems from the high conservation of its signaling pathways, lower genetic redundancy, short life cycle, genetic amenability, and ease of maintenance. Several cell signaling pathways in Drosophila have been used for cancer drug development. The efficacy of combination therapy and uptake/bioavailability of drugs have also been studied. ... The advantages and limitations of the model are discussed."

Thursday, June 2, 2016

Fat flies don't glow -- Drosophila model for obesity-related research

Men TT, Thanh DN, Yamaguchi M, Suzuki T, Hattori G, Arii M, Huy NT, Kamei K. A Drosophila Model for Screening Antiobesity Agents. Biomed Res Int. 2016;2016:6293163. PMID: 27247940.

From the abstract: "... The brummer (bmm) gene in Drosophila melanogaster is known to be homologous with human adipocyte triglyceride lipase, which is related to the regulation of lipid storage. We established a Drosophila model for monitoring bmm expression by introducing the green fluorescent protein (GFP) gene as a downstream reporter of the bmm promoter. ... The Drosophila flies given high-glucose diets showed higher lipid contents, indicating the obesity phenotype; this was suggested by a weaker intensity of the GFP signal as well as reduced bmm mRNA expression. These results demonstrated that the transgenic Drosophila model established in this study is useful for screening antiobesity agents. We also report the effects of oral administration of histone deacetylase inhibitors and some vegetables on the bmm promoter activity."

Tuesday, May 31, 2016

Using the fly system to explore the role of glia in neurological diseases (review)

Zwarts L, Van Eijs F, Callaerts P. Glia in Drosophila behavior. J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2015 Sep;201(9):879-93. PMID: 25336160.

From the abstract: "Glial cells constitute about 10% of the Drosophila nervous system. The development of genetic and molecular tools has helped greatly in defining different types of glia. ... We here summarize recent work describing the role of glia in normal behavior and in Drosophila models for neurological and behavioral disorders."

Monday, May 16, 2016

New fly model of Parkinsons Disease

Merzetti EM, Staveley BE. Altered expression of CG5961, a putative Drosophila melanogaster homologue of FBXO9, provides a new model of Parkinson disease. Genet Mol Res. 2016 May 9;15(2). PMID: 27173356.

Monday, May 9, 2016

Confidence in numbers: work in 3 model organisms supports gene-disease link in humans

Gan-Or Z, Bouslam N, Birouk N, Lissouba A, Chambers DB, Vérièpe J, Androschuck A, Laurent SB, Rochefort D, Spiegelman D, Dionne-Laporte A, Szuto A, Liao M, Figlewicz DA, Bouhouche A, Benomar A, Yahyaoui M, Ouazzani R, Yoon G, Dupré N, Suchowersky O, Bolduc FV, Parker JA, Dion PA, Drapeau P, Rouleau GA, Bencheikh BO. Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia. Am J Hum Genet. 2016 May 5;98(5):1038-46. PMID: 27153400.

From the abstract: "Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner. In the current study, we performed whole-exome sequencing to analyze a total of nine affected individuals in three families with autosomal-recessive HSP. Rare homozygous and compound-heterozygous nonsense, missense, frameshift, and splice-site mutations in CAPN1 were identified ... CAPN1 encodes calpain 1, a protease that is widely present in the CNS. ... Three models of calpain 1 deficiency were further studied. In Caenorhabditis elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction and degeneration. Similarly, loss-of-function of the Drosophila melanogaster ortholog calpain B caused locomotor defects and axonal anomalies. Knockdown of calpain 1a, a CAPN1 ortholog in Danio rerio, resulted in abnormal branchiomotor neuron migration and disorganized acetylated-tubulin axonal networks in the brain. The identification of mutations in CAPN1 in HSP expands our understanding of the disease causes and potential mechanisms."

Friday, April 8, 2016

Review of fly research related to type 2 diabetes

Alfa RW, Kim SK. Using Drosophila to discover mechanisms underlying type 2 diabetes. Dis Model Mech. 2016 Apr 1;9(4):365-76. PMID: 27053133.

From the abstract: "Mechanisms of glucose homeostasis are remarkably well conserved between the fruit fly Drosophila melanogaster and mammals. From the initial characterization of insulin signaling in the fly came the identification of downstream metabolic pathways for nutrient storage and utilization. Defects in these pathways lead to phenotypes that are analogous to diabetic states in mammals. These discoveries have stimulated interest in leveraging the fly to better understand the genetics of type 2 diabetes mellitus in humans. ... Here, we examine results from studies modeling metabolic disease in the fruit fly and compare findings to proposed mechanisms for diabetic phenotypes in mammals. We provide a systematic framework for assessing the contribution of gene candidates to insulin-secretion or insulin-resistance pathways relevant to diabetes pathogenesis."

Monday, March 28, 2016

Fly models used to validate association of proteins with Alzheimers disease

Minjarez B, Calderón-González KG, Rustarazo ML, Herrera-Aguirre ME, Labra-Barrios ML, Rincon-Limas DE, Del Pino MM, Mena R, Luna-Arias JP. Identification of proteins that are differentially expressed in brains with Alzheimer's disease using iTRAQ labeling and tandem mass spectrometry. J Proteomics. 2016 Mar 21. PMID: 27012543.

From the abstract: "Alzheimer's disease is one of the leading causes of dementia in the elderly. It is considered the result of complex events involving both genetic and environmental factors. To gain further insights into this complexity, we quantitatively analyzed the proteome of cortex region of brains from patients diagnosed with Alzheimer's disease, using a bottom-up proteomics approach. ... We used Drosophila to validate some of the hits ... We manipulated their homolog genes in Drosophila models of Aβ- and Tau-induced pathology. We found proteins that can either modify Aβ toxicity, Tau toxicity or both, suggesting specific interactions with different pathways. This approach illustrates the potential of Drosophila to validate hits after MS studies and suggest that model organisms should be included in the pipeline to identify relevant targets for Alzheimer's disease. ... With this approach, Sideroflexin and Phosphoglucomutase-1 were identified as novel proteins connected with Alzheimer's disease."

Thursday, March 24, 2016

Drosophila studies help implicate ALFY gene in human primary microcephaly

Kadir R, Harel T, Markus B, Perez Y, Bakhrat A, Cohen I, Volodarsky M, Feintsein-Linial M, Chervinski E, Zlotogora J, Sivan S, Birnbaum RY, Abdu U, Shalev S, Birk OS. ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size. PLoS Genet. 2016 Mar 23;12(3):e1005919. PMID: 27008544.

From the abstract: "Primary microcephaly is a congenital neurodevelopmental disorder of reduced head circumference and brain volume ... We now show ... that a dominant mutation in ALFY, encoding an autophagy scaffold protein, causes human primary microcephaly. We demonstrate the dominant effect of the mutation in drosophila: transgenic flies harboring the human mutant allele display small brain volume, recapitulating the disease phenotype ..."

Saturday, February 27, 2016

Drosophila model of Alexander disease used to identify cholinergic signaling as potential therapeutic target

Wang L, Hagemann TL, Messing A, Feany MB. An In Vivo Pharmacological Screen Identifies Cholinergic Signaling as a Therapeutic Target in Glial-Based Nervous System Disease. J Neurosci. 2016 Feb 3;36(5):1445-55. PMID: 26843629; PMCID: PMC4737762.

From the abstract: "... Using a simple Drosophila model of Alexander disease, we performed a moderate throughput chemical screen of FDA-approved drugs and natural compounds, and found that reducing muscarinic cholinergic signaling ameliorated clinical symptoms and oxidative stress in Alexander disease model flies and mice. Our work demonstrates that small animal models are valuable screening tools for therapeutic compound identification in complex human diseases and that existing drugs can be a valuable resource for drug discovery given their known pharmacological and safety profiles."

Wondering what is Alexander disease? Read about this rare nervous system disease at NIH Genetics Home Reference.

Tuesday, February 23, 2016

Detailed phenotypic analysis of flies lacking activity of Nf1, which is associated with neurofibromatosis

King LB, Koch M, Murphy K, Velazquez Y, Ja WW, Tomchik SM. Neurofibromin Loss of Function Drives Excessive Grooming in Drosophila. G3 (Bethesda). 2016 Feb 19. PMID: 26896440.

From the abstract: "Neurofibromatosis I is a common genetic disorder that results in tumor formation and predisposes individuals to a range of cognitive/behavioral symptoms, including deficits in attention, visuospatial skills, learning, language development, sleep, and autism spectrum disorder-like traits. ... Drosophila provide a powerful platform to investigate the signaling cascades upstream and downstream of Nf1, and the fly model exhibits similar behavioral phenotypes to mammalian models. In order to understand how loss of Nf1 affects motor behavior in flies, we combined traditional activity monitoring with video analysis of grooming behavior. In nf1 mutants, spontaneous grooming was increased up to 7x. ... Overall, these data suggest that loss of nf1 produces excessive activity that is manifested as increased grooming, providing a platform to dissect the molecular genetics of neurofibromin signaling across neuronal circuits."

Saturday, February 20, 2016

Cutting-edge techniques used in Drosophila help elucidate mechanisms of amphetamine transport in cells

Freyberg Z, Sonders MS, Aguilar JI, Hiranita T, Karam CS, Flores J, Pizzo AB, Zhang Y, Farino ZJ, Chen A, Martin CA, Kopajtic TA, Fei H, Hu G, Lin YY, Mosharov EV, McCabe BD, Freyberg R, Wimalasena K, Hsin LW, Sames D, Krantz DE, Katz JL, Sulzer D, Javitch JA. Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain. Nat Commun. 2016 Feb 16;7:10652. PMID: 26879809.

From the abstract: "Amphetamines elevate extracellular dopamine, but the underlying mechanisms remain uncertain. Here we show in rodents that acute pharmacological inhibition of the vesicular monoamine transporter (VMAT) blocks amphetamine-induced locomotion and self-administration ... To study VMAT's role .. we have used novel genetic, pharmacological and optical approaches in Drosophila melanogaster. ... we find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects."

New double-mutant fly model of Adrenoleukodystrophy (ALD) "best paradigm to date"

Sivachenko A, Gordon HB, Kimball SS, Gavin EJ, Bonkowsky JL, Letsou A. Neurodegeneration in a Drosophila model of Adrenoleukodystrophy: the roles of the bubblegum and double bubble acyl-CoA synthetases. Dis Model Mech. 2016 Feb 18. pii: dmm.022244. PMID: 26893370.

From the abstract: "Debilitating neurodegenerative conditions with metabolic origins affect millions of individuals worldwide. Still, for most of these neurometabolic disorders ... novel animal models are needed for elucidation of disease pathology and identification of potential therapeutic agents. To date, metabolic neurodegenerative disease has been modeled in animals with only limited success, in part because existing models constitute analyses of single mutants ... We show that the Drosophila bubblegum (bgm) and double bubble (dbb) genes have overlapping functions, and that the consequences of ... double knockout in the fly brain are profound ... providing the best paradigm to date for an animal model of Adrenoleukodystrophy (ALD), a fatal childhood neurodegenerative disease associated with the accumulation of very long chain fatty acids. ... in an extension of our model system to the study of human disease, we describe our identification of a leukodystrophy patient who harbors a rare mutation in a human homologue of Bgm and Dbb: the SLC27a6-encoded very-long-chain acyl-CoA synthetase."

Monday, February 15, 2016

New fly model -- fly eye used to study viral-induced cancers

Shirinian M, Kambris Z, Hamadeh L, Grabbe C, Journo C, Mahieux R, Bazarbachi A. A Transgenic Drosophila melanogaster Model To Study Human T-Lymphotropic Virus Oncoprotein Tax-1-Driven Transformation In Vivo. J Virol. 2015 Aug;89(15):8092-5. PMID: 25995252; PMCID: PMC4505646.

Catching up (or at least, beginning to) on neurodegenerative disease-related fly papers


Foriel S, Willems P, Smeitink J, Schenck A, Beyrath J. Mitochondrial diseases: Drosophila melanogaster as a model to evaluate potential therapeutics. Int J Biochem Cell Biol. 2015 Jun;63:60-5. PMID: 25666557.

Repalli J. Translocator protein (TSPO) role in aging and Alzheimer's disease. Curr Aging Sci. 2014;7(3):168-75. PMID: 25495567; PMCID: PMC4435228.

Research papers

Wu K, Liu J, Zhuang N, Wang T. UCP4A protects against mitochondrial dysfunction and degeneration in pink1/parkin models of Parkinson's disease. FASEB J. 2014 Dec;28(12):5111-21. PMID: 25145627.

Vorobyeva AG, Lee R, Miller S, Longen C, Sharoni M, Kandelwal PJ, Kim FJ, Marenda DR, Saunders AJ. Cyclopamine modulates γ-secretase-mediated cleavage of amyloid precursor protein by altering its subcellular trafficking and lysosomal degradation. J Biol Chem. 2014 Nov 28;289(48):33258-74. PMID: 25281744; PMCID: PMC4246084.

Butzlaff M, Hannan SB, Karsten P, Lenz S, Ng J, Voßfeldt H, Prüßing K, Pflanz R, Schulz JB, Rasse T, Voigt A. Impaired retrograde transport by the Dynein/Dynactin complex contributes to Tau-induced toxicity. Hum Mol Genet. 2015 Jul 1;24(13):3623-37. PMID: 25794683.

Rossor AM, Oates EC, Salter HK, Liu Y, Murphy SM, Schule R, Gonzalez MA, Scott M, Phadke R, Sewry CA, Houlden H, Jordanova A, Tournev I, Chamova T, Litvinenko I, Zuchner S, Herrmann DN, Blake J, Sowden JE, Acsadi G, Rodriguez ML, Menezes MP, Clarke NF, Auer Grumbach M, Bullock SL, Muntoni F, Reilly MM, North KN. Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2. Brain. 2015 Feb;138(Pt 2):293-310. PMID: 25497877; PMCID: PMC4306822. ---See also comment and reply.

Doll CA, Broadie K. Activity-dependent FMRP requirements in development of the neural circuitry of learning and memory. Development. 2015 Apr 1;142(7):1346-56. PMID: 25804740; PMCID: PMC4378248.

Sanhueza M, Chai A, Smith C, McCray BA, Simpson TI, Taylor JP, Pennetta G. Network analyses reveal novel aspects of ALS pathogenesis. PLoS Genet. 2015 Mar 31;11(3):e1005107. PMID: 25826266; PMCID: PMC4380362.

Dalui S, Bhattacharyya A. Herbicide paraquat induces sex-specific variation of neuroinflammation and neurodegeneration in Drosophila melanogaster. Indian J Biochem Biophys. 2014 Dec;51(6):567-73. PubMed PMID: 25823231.

Jimenez-Sanchez M, Lam W, Hannus M, Sönnichsen B, Imarisio S, Fleming A, Tarditi A, Menzies F, Ed Dami T, Xu C, Gonzalez-Couto E, Lazzeroni G, Heitz F, Diamanti D, Massai L, Satagopam VP, Marconi G, Caramelli C, Nencini A, Andreini
M, Sardone GL, Caradonna NP, Porcari V, Scali C, Schneider R, Pollio G, O'Kane CJ, Caricasole A, Rubinsztein DC. siRNA screen identifies QPCT as a draggable target for Huntington's disease. Nat Chem Biol. 2015 May;11(5):347-54. PMID: 25848931; PMCID: PMC4696152.

Liu L, Zhang K, Sandoval H, Yamamoto S, Jaiswal M, Sanz E, Li Z, Hui J, Graham BH, Quintana A, Bellen HJ. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell. 2015 Jan 15;160(1-2):177-90. PMID: 25594180; PMCID: PMC4377295.

Wen X, Tan W, Westergard T, Krishnamurthy K, Markandaiah SS, Shi Y, Lin S, Shneider NA, Monaghan J, Pandey UB, Pasinelli P, Ichida JK, Trotti D. Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron. 2014 Dec 17;84(6):1213-25. PMID: 25521377; PMCID: PMC4632245.

Ochaba J, Lukacsovich T, Csikos G, Zheng S, Margulis J, Salazar L, Mao K, Lau AL, Yeung SY, Humbert S, Saudou F, Klionsky DJ, Finkbeiner S, Zeitlin SO, Marsh JL, Housman DE, Thompson LM, Steffan JS. Potential function for the Huntington protein as a scaffold for selective autophagy. Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16889-94. PMID: 25385587; PMCID: PMC4250109.

Wade AR, Elliott CJ. Could the detection of visual disturbances associated with Parkinson's disease genes in flies lead to new treatments for the disease? Neurodegener Dis Manag. 2014;4(4):291-3. PMID: 25313984.

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Tests in fly help shed light on mechanisms relevant to muscular dystrophy

Dialynas G, Shrestha OK, Ponce JM, Zwerger M, Thiemann DA, Young GH, Moore SA, Yu L, Lammerding J, Wallrath LL. Myopathic lamin mutations cause reductive stress and activate the nrf2/keap-1 pathway. PLoS Genet. 2015 May 21;11(5):e1005231. PMID: 25996830; PMCID: PMC4440730.

From the abstract: "Mutations in the human LMNA gene cause muscular dystrophy by mechanisms that are incompletely understood. The LMNA gene encodes A-type lamins, intermediate filaments that form a network underlying the inner nuclear membrane, providing structural support for the nucleus and organizing the genome. To better understand the pathogenesis caused by mutant lamins, we performed a structural and functional analysis on LMNA missense mutations identified in muscular dystrophy patients. These mutations perturb the tertiary structure of the conserved A-type lamin Ig-fold domain. To identify the effects of these structural perturbations on lamin function, we modeled these mutations in Drosophila Lamin C and expressed the mutant lamins in muscle. ... Affected muscles had cytoplasmic aggregation of lamins and additional nuclear envelope proteins. Transcription profiling revealed upregulation of many Nrf2 target genes. ... Elevated p62/SQSTM1 and nuclear enrichment of Nrf2 were identified in muscle biopsies from the corresponding muscular dystrophy patients, validating the disease relevance of our Drosophila model. Thus, novel connections were made between mutant lamins and the Nrf2 signaling pathway, suggesting new avenues of therapeutic intervention that include regulation of protein folding and metabolism, as well as maintenance of redox homoeostasis."