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."
Wednesday, December 28, 2016
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 ..."
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."
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."
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."
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."
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."
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."
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 ..."
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. ..."
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."
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."
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."
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."
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. ..."
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."
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."
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."
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."
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."
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. ..."
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."
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.
ALS
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.
FTD/ALS
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.
HD, AD & PD
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.
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.
ALS
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.
FTD/ALS
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.
HD, AD & PD
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.
ALS
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.
FTD/ALS
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.
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.
ALS
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.
FTD/ALS
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."
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."
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."
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."
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. ..."
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."
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."
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."
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. ..."
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."
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."
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."
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."
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."
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