Monday, July 17, 2017

Fly research and neurodegenerative diseases

Research articles related to ALS and Alzheimer's disease

Baldwin KR, Godena VK, Hewitt VL, Whitworth AJ. Axonal transport defects are a common phenotype in Drosophila models of ALS. Hum Mol Genet. 2016 Jun 15;25(12):2378-2392. Epub 2016 Apr 7. PMID: 27056981; PMCID: PMC5181624.

From the abstract: "Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of motor neurons resulting in a catastrophic loss of motor function. Current therapies are severely limited owing to a poor mechanistic understanding of the pathobiology. Mutations in a large number of genes have now been linked to ALS, including SOD1, TARDBP (TDP-43), FUS and C9orf72. Functional analyses of these genes and their pathogenic mutations have provided great insights into the underlying disease mechanisms. Defective axonal transport is hypothesized to be a key factor in the selective vulnerability of motor nerves ... Here, we assessed the axonal transport of different cargos in multiple Drosophila models of ALS. ... These results further support defects in axonal transport as a common factor in models of ALS that may contribute to the pathogenic process."

Bernstein AI, Lin Y, Street RC, Lin L, Dai Q, Yu L, Bao H, Gearing M, Lah JJ, Nelson PT, He C, Levey AI, Mullé JG, Duan R, Jin P. 5-Hydroxymethylation-associated epigenetic modifiers of Alzheimer's disease modulate Tau-induced neurotoxicity. Hum Mol Genet. 2016 Jun 15;25(12):2437-2450. PMID: 27060332; PMCID: PMC5181627.

From the abstract: "Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive deterioration of cognitive function. Pathogenesis of AD is incompletely understood; evidence suggests a role for epigenetic regulation, in particular the cytosine modifications 5-methylcytosine and 5-hydroxymethylcytosine (5hmC). 5hmC is enriched in the nervous system and displays neurodevelopment and age-related changes. To determine the role of 5hmC in AD, we performed genome-wide analyses of 5hmC in DNA from prefrontal cortex of post-mortem AD patients, and RNA-Seq to correlate changes in 5hmC with transcriptional changes. We identified 325 genes containing differentially hydroxymethylated loci (DhMLs) in both discovery and replication datasets. ... Finally, using an existing AD fly model, we showed some of these genes modulate AD-associated toxicity. ..."

And a review related to Parkinson's disease

Voigt A, Berlemann LA, Winklhofer KF. The mitochondrial kinase PINK1: functions beyond mitophagy. J Neurochem. 2016 Oct;139 Suppl 1:232-239. PMID: 27251035.

From the abstract: "Mutations in the genes encoding the mitochondrial kinase PINK1 and the E3 ubiquitin ligase Parkin cause autosomal recessive Parkinson's disease (PD). Pioneering work in Drosophila melanogaster revealed that the loss of PINK1 or Parkin function causes similar phenotypes including dysfunctional mitochondria. Further research showed that PINK1 can act upstream of Parkin in a mitochondrial quality control pathway to induce removal of damaged mitochondria in a process called mitophagy. ... In this review, we summarize and discuss the functional roles of PINK1 in maintaining mitochondrial integrity, eliminating damaged mitochondria, and promoting cell survival. This article is part of a special issue on Parkinson disease."

Fly research & heart disease -- a review

Ma L. Can the Drosophila model help in paving the way for translational medicine in heart failure? Biochem Soc Trans. 2016 Oct 15;44(5):1549-1560. Review. PMID: 27911738.

Wednesday, July 12, 2017

No internal skeleton? No problem. The fly grainyhead gene informs our understanding of craniofacial defects

Carpinelli MR, de Vries ME, Jane SM, Dworkin S. Grainyhead-like Transcription Factors in Craniofacial Development. J Dent Res. 2017 Jul 1:22034517719264. PMID: 28697314.

The abstract: "Craniofacial development in vertebrates involves the coordinated growth, migration, and fusion of several facial prominences during embryogenesis, processes governed by strict genetic and molecular controls. A failure in any of the precise spatiotemporal sequences of events leading to prominence fusion often leads to anomalous facial, skull, and jaw formation-conditions termed craniofacial defects (CFDs). Affecting approximately 0.1% to 0.3% of live births, CFDs are a highly heterogeneous class of developmental anomalies, which are often underpinned by genetic mutations. Therefore, identifying novel disease-causing mutations in genes that regulate craniofacial development is a critical prerequisite to develop new preventive or therapeutic measures. The Grainyhead-like (GRHL) transcription factors are one such gene family, performing evolutionarily conserved roles in craniofacial patterning. The antecedent member of this family, Drosophila grainyhead (grh), is required for head skeleton development in fruit flies, loss or mutation of Grhl family members in mouse and zebrafish models leads to defects of both maxilla and mandible, and recently, mutations in human GRHL3 have been shown to cause or contribute to both syndromic (Van Der Woude syndrome) and nonsyndromic palatal clefts. In this review, we summarize the current knowledge regarding the craniofacial-specific function of the Grainyhead-like family in multiple model species, identify some of the major target genes regulated by the Grhl transcription factors in craniofacial patterning, and, by examining animal models, draw inferences as to how these data will inform the likely roles of GRHL factors in human CFDs comprising palatal clefting. By understanding the molecular networks regulated by Grhl2 and Grhl3 target genes in other systems, we can propose likely pathways that mediate the effects of these transcription factors in human palatogenesis."

Monday, July 10, 2017

Metal-related diseases studied using Drosophila

Calap-Quintana P, González-Fernández J, Sebastiá-Ortega N, Llorens JV, Moltó MD. Drosophila melanogaster Models of Metal-Related Human Diseases and Metal Toxicity. Int J Mol Sci. 2017 Jul 6;18(7). pii: E1456. PMID: 28684721.

From the abstract: "Iron, copper and zinc are transition metals essential for life ... Organisms have evolved to acquire metals from nutrition and to maintain adequate levels of each metal to avoid damaging effects associated with its deficiency, excess or misplacement. ... many orthologues of the human metal-related genes having been identified and characterized in Drosophila melanogaster. Drosophila has gained appreciation as a useful model for studying human diseases, including those caused by mutations in pathways controlling cellular metal homeostasis. ... This review recapitulates the metabolism of the principal transition metals, namely iron, zinc and copper, in Drosophila and the utility of this organism as an experimental model to explore the role of metal dyshomeostasis in different human diseases. Finally, a summary of the contribution of Drosophila as a model for testing metal toxicity is provided."

Wednesday, June 7, 2017

Review highlights successful fly research collaborations with clinical impact

Chao HT, Liu L, Bellen HJ. Building dialogues between clinical and biomedical research through cross-species collaborations. Semin Cell Dev Biol. 2017 Jun 1. PMID: 28579453.

The abstract: "Today, biomedical science is equipped with an impressive array of technologies and genetic resources that bolster our basic understanding of fundamental biology and enhance the practice of modern medicine by providing clinicians with a diverse toolkit to diagnose, prognosticate, and treat a plethora of conditions. Many significant advances in our understanding of disease mechanisms and therapeutic interventions have arisen from fruitful dialogues between clinicians and biomedical research scientists. However, the increasingly specialized scientific and medical disciplines, globalization of science and technology, and complex datasets often hinder the development of effective interdisciplinary collaborations between clinical medicine and biomedical research. The goal of this review is to provide examples of diverse strategies to enhance communication and collaboration across diverse disciplines. First, we discuss examples of efforts to foster interdisciplinary collaborations at institutional and multi-institutional levels. Second, we explore resources and tools for clinicians and research scientists to facilitate effective bi-directional dialogues. Third, we use our experiences in neurobiology and human genetics to highlight how communication between clinical medicine and biomedical research lead to effective implementation of cross-species model organism approaches to uncover the biological underpinnings of health and disease."

Friday, May 19, 2017

Flies used to test impact of retinal disease-relevant mutations on function of Crumbs family proteins

Pellikka M, Tepass U. Unique cell biological profiles of retinal disease-causing missense mutations in the polarity protein crumbs. J Cell Sci. 2017 May 17. pii: jcs.197178. PMID: 28515229.

From the abstract: "Mutations in human CRB1 are a major cause of retinal disease that lead to blindness. CRB1 is a transmembrane protein found in the inner segment of photoreceptor cells (PRCs) and the apical membrane of Müller glia. The function of the extracellular region of CRB1 is poorly understood although more than 80 disease-causing missense mutations have been mapped to it. We have recreated four mutations in Drosophila Crumbs (Crb) that affect different extracellular domains. ... The mutant Crb isoforms showed a remarkable diversity in protein abundance, subcellular distribution, and ability to rescue the lack of endogenous Crb, elicit a gain-of-function phenotype, or promote PRC degeneration. Interestingly, although expression of mutant isoforms rescued developmental defects of crb mutants substantially, they accelerated PRC degeneration compared to retinas that lack Crb ... Several Crb mutant proteins accumulated abnormally in the rhabdomere and affected rhodopsin trafficking, suggesting that abnormal rhodopsin physiology contributes to Crb/CRB1-dependent retinal degeneration."

Tuesday, May 16, 2017

Experiments in flies contribute to study of Renpenning syndrome

Zhang XY, Qi J, Shen YQ, Liu X, Liu A, Zhou Z, Han J, Zhang ZC. Mutations of PQBP1 in Renpenning syndrome promote ubiquitin-mediated degradation of FMRP and cause synaptic dysfunction. Hum Mol Genet. 2017 Mar 1;26(5):955-968. PMID: 28073926.

From the abstract:
"Renpenning syndrome is a group of X-linked intellectual disability syndromes caused by mutations in human polyglutamine-binding protein 1 (PQBP1) gene. ... In this study, we examine the cellular and synaptic functions of the most common mutations found in the patients ... In Drosophila neuromuscular junction model, PQBP1 c.463_464dupAG transgenic flies showed remarkable defects of synaptic over-growth, which can be rescued by exogenously expressing dFMRP. Our data strongly support a gain-of-function pathogenic mechanism of PQBP1 c.459_462delAGAG and c.463_464dupAG mutations, and suggest that therapeutic strategies to restore FMRP function may be beneficial for those patients."

Crystal structure of fly protein reveals new functional information relevant to epilepsy and DOOR syndrome

Fischer B, Lüthy K, Paesmans J, De Koninck C, Maes I, Swerts J, Kuenen S, Uytterhoeven V, Verstreken P, Versées W. Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function. Nat Struct Mol Biol. 2016 Nov;23(11):965-973. PMID: 27669036.

From the abstract: "Mutations in TBC1D24 cause severe epilepsy and DOORS syndrome, but the molecular mechanisms underlying these pathologies are unresolved. We solved the crystal structure of the TBC domain of the Drosophila ortholog Skywalker, revealing an unanticipated cationic pocket conserved among TBC1D24 homologs. ... The most prevalent patient mutations affect the phosphoinositide-binding pocket and inhibit lipid binding. ... Hence, we discovered that a TBC domain affected by clinical mutations directly binds phosphoinositides through a cationic pocket and that phosphoinositide binding is critical for presynaptic function."

Thursday, April 20, 2017

Review article: the fly as "powerful system for the study of human genetic disease"

Chow CY, Reiter LT. Etiology of Human Genetic Disease on the Fly. Trends Genet. 2017 Apr 15. pii: S0168-9525(17)30051-3. PMID: 28420493.

Abstract: "The model organism Drosophila melanogaster has been at the forefront of genetic studies since before the discovery of DNA. Although human disease modeling in flies may still be rather novel, recent advances in genetic tool design and genome sequencing now confer huge advantages in the fly system when modeling human disease. In this review, we focus on new genomic tools for human gene variant analysis; new uses for the Drosophila Genetic Reference Panel (DGRP) in detection of background alleles that influence a phenotype; and several examples of how multigenic conditions, both complex disorders and duplication and/or deletion syndromes, can be effectively studied in the fly model system. Fruit flies are a far cry from the quaint genetic model of the past, but rather, continue to evolve as a powerful system for the study of human genetic disease."

Monday, April 10, 2017

Drosophila genetic screen identifies new candidate Alzheimer's-related genes

Belfiori-Carrasco LF, Marcora MS, Bocai NI, Ceriani MF, Morelli L, Castaño EM. A Novel Genetic Screen Identifies Modifiers of Age-Dependent Amyloid β Toxicity in the Drosophila Brain. Front Aging Neurosci. 2017 Mar 14;9:61. PMID: 28352227; PMCID: PMC5349081.

From the abstract: "The accumulation of amyloid β peptide (Aβ) in the brain of Alzheimer's disease (AD) patients begins many years before clinical onset. Such process has been proposed to be pathogenic through the toxicity of Aβ soluble oligomers leading to synaptic dysfunction, phospho-tau aggregation and neuronal loss. Yet, a massive accumulation of Aβ can be found in approximately 30% of aged individuals with preserved cognitive function. Therefore, within the frame of the "amyloid hypothesis", compensatory mechanisms and/or additional neurotoxic or protective factors need to be considered and investigated. Here we describe a modifier genetic screen in Drosophila designed to identify genes that modulate toxicity of Aβ42 in the CNS. ... Our screen is the first to take into account all of the following features, relevant to sporadic AD: (1) pan-neuronal expression of wild-type Aβ42; (2) a quantifiable complex behavior; (3) Aβ neurotoxicity associated with progressive accumulation of the peptide; and (4) improvement or worsening of climbing ability only evident in aged animals. One hundred and ninety-nine deficiency (Df) lines accounting for ~6300 genes were analyzed. ... So far, we have validated CG11796 and identified CG17249 as a strong candidate (whose human orthologs are HPD and PRCC, respectively) by using RNAi or mutant hemizygous lines. ... These previously undetected modifiers of Aβ42 neurotoxicity in Drosophila warrant further study to validate their possible role and significance in the pathogenesis of sporadic AD."

Thursday, April 6, 2017

Parallel studies in human induced pluripotent stem cells and Drosophila identify a potential new target for development of possible therapies for Parkinson's Disease

Zanon A, Kalvakuri S, Rakovic A, Foco L, Guida M, Schwienbacher C, Serafin A, Rudolph F, Trilck M, Grünewald A, Stanslowsky N, Wegner F, Giorgio V, Lavdas AA, Bodmer R, Pramstaller PP, Klein C, Hicks AA, Pichler I, Seibler P. SLP-2 interacts with Parkin in mitochondria and prevents mitochondrial dysfunction in Parkin-deficient human iPSC-derived neurons and Drosophila. Hum Mol Genet. 2017 Apr 3. PMID: 28379402.

From the abstract: "Mutations in the Parkin gene (PARK2) have been linked to a recessive form of Parkinson's disease (PD) characterized by the loss of dopaminergic neurons in the substantia nigra. Deficiencies of mitochondrial respiratory chain complex I activity have been observed in the substantia nigra of PD patients, and loss of Parkin results in the reduction of complex I activity shown in various cell and animal models. Using co-immunoprecipitation and proximity ligation assays on endogenous proteins, we demonstrate that Parkin interacts with mitochondrial Stomatin-like protein 2 (SLP-2), which also binds the mitochondrial lipid cardiolipin and functions in the assembly of respiratory chain proteins. ... In-vivo Drosophila studies showed a genetic interaction of Parkin and SLP-2, and further, tissue-specific or global overexpression of SLP-2 transgenes rescued parkin mutant phenotypes ... The physical and genetic interaction between Parkin and SLP-2 and the compensatory potential of SLP-2 suggest a functional epistatic relationship to Parkin and a protective role of SLP-2 in neurons. This finding places further emphasis on the significance of Parkin for the maintenance of mitochondrial function in neurons and provides a novel target for therapeutic strategies."

Friday, March 24, 2017

Aggression among flies as a model behavior for studies related to human neurological disorders

Zwarts L, Vulsteke V, Buhl E, Hodge JJ, Callaerts P. SlgA, the homologue of the human schizophrenia associated PRODH gene, acts in clock neurons to regulate Drosophila aggression. Dis Model Mech. 2017 Mar 22. pii: dmm.027151. PMID: 28331058.

From the abstract: "Mutations in proline dehydrogenase (PRODH) are linked to behavioral alterations in schizophrenia ... We here establish a Drosophila model to study the role of PRODH in behavioral disorders. We ... show that knock-down and overexpression of human PRODH and slgA in the lateral neurons ventral (LNv) lead to altered aggressive behavior. SlgA acts in an isoform-specific manner and is regulated by casein kinase II (CkII). Our data suggest that these effects are, at least partially, due to effects on mitochondrial function. We thus show that precise regulation of proline metabolism is essential to drive normal behavior and we identify Drosophila aggression as a model behavior relevant for the study of mechanisms impaired in neuropsychiatric disorders."

Thursday, March 23, 2017

Study of Ets96B/ETV5 connects obesity and bipolar disorder at a molecular level

Williams MJ, Klockars A, Eriksson A, Voisin S, Dnyansagar R, Wiemerslage L, Kasagiannis A, Akram M, Kheder S, Ambrosi V, Hallqvist E, Fredriksson R, Schiöth HB. The Drosophila ETV5 Homologue Ets96B: Molecular Link between Obesity and Bipolar Disorder. PLoS Genet. 2016 Jun 9;12(6):e1006104. PubMed PMID: 27280443; PubMed Central PMCID: PMC4900636.

From the abstract: "Several reports suggest obesity and bipolar disorder (BD) share some physiological and behavioural similarities. ... Here we demonstrate, using whole transcriptome analysis, that Drosophila Ets96B, homologue of obesity-linked gene ETV5, regulates cellular systems associated with obesity and BD. Consistent with a role in obesity and BD, loss of nervous system Ets96B during development increases triacylglyceride concentration, while inducing a heightened startle-response, as well as increasing hyperactivity and reducing sleep. Of notable interest, mouse Etv5 and Drosophila Ets96B are expressed in dopaminergic-rich regions, and loss of Ets96B specifically in dopaminergic neurons recapitulates the metabolic and behavioural phenotypes. Moreover, our data indicate Ets96B inhibits dopaminergic-specific neuroprotective systems. Additionally, we reveal that multiple SNPs in human ETV5 link to body mass index (BMI) and BD, providing further evidence for ETV5 as an important and novel molecular intermediate between obesity and BD. ... a connection between the obesity-linked gene ETV5 and bipolar disorder emphasizes a functional relationship between obesity and BD at the molecular level."

Review article addresses the question, Can flies help us find plant-based medicines?

Panchal K, Tiwari AK. Drosophila melanogaster "a potential model organism" for identification of pharmacological properties of plants/plant-derived components. Biomed Pharmacother. 2017 Mar 18;89:1331-1345. PubMed PMID: 28320100.

From the abstract: "Plants/plant-derived components have been used from ancient times to treat/cure several human diseases. ... long time consumption cause serious health concerns such as hyperallergic reactions, liver damage, etc. ... The current review focuses on the potential of Drosophila melanogaster for the identification of medicinal/pharmacological properties associated with plants/plant-derived components."

Tuesday, January 24, 2017

Results of a study in Drosophila suggest the possible relevance of neuronal aneuploidy to Tau-associated neurodegeneration

Malmanche N, Dourlen P, Gistelinck M, Demiautte F, Link N, Dupont C, Vanden Broeck L, Werkmeister E, Amouyel P, Bongiovanni A, Bauderlique H, Moechars D, Royou A, Bellen HJ, Lafont F, Callaerts P, Lambert JC, Dermaut B. Developmental Expression of 4-Repeat-Tau Induces Neuronal Aneuploidy in Drosophila Tauopathy Models. Sci Rep. 2017 Jan 23;7:40764. PMID: 28112163.

From the abstract: "Tau-mediated neurodegeneration in Alzheimer's disease and tauopathies is generally assumed to start in a normally developed brain. However, several lines of evidence suggest that impaired Tau isoform expression during development could affect mitosis and ploidy in post-mitotic differentiated tissue. ... Here, we used genetic and cellular tools to study the link between 3R and 4R-Tau isoform expression, mitotic progression in neuronal progenitors and post-mitotic neuronal survival. Our results illustrated that the severity of Tau-induced adult phenotypes depends on 4R-Tau isoform expression during development. ... we found a high level of aneuploidy in post-mitotic differentiated tissue. ... our results suggested that neurodegeneration could be in part linked to neuronal aneuploidy caused by 4R-Tau expression during brain development."

Monday, January 23, 2017

Using flies to functionally validate candidate heart disease-related genes

Zhu JY, Fu Y, Nettleton M, Richman A, Han Z. High throughput in vivo functional validation of candidate congenital heart disease genes in Drosophila. Elife. 2017 Jan 13;6. pii: e22617. PMID: 28084990.

From the abstract: "... We developed a Drosophila-based functional system to screen candidate disease genes identified from Congenital Heart Disease (CHD) patients. 134 genes were tested in the Drosophila heart using RNAi-based gene silencing. Quantitative analyses of multiple cardiac phenotypes demonstrated essential structural, functional, and developmental roles for more than 70 genes ... We also demonstrated the use of Drosophila to evaluate cardiac phenotypes resulting from specific, patient-derived alleles of candidate disease genes. ... This approach has the potential to facilitate development of precision medicine approaches for CHD and other diseases associated with genetic factors."

Review of drug discovery using model organisms including Drosophila

Strange K. Drug Discovery in Fish, Flies, and Worms. ILAR J. 2016 Dec;57(2):133-143. PMID: 28053067.

From the abstract: "Nonmammalian model organisms ... provide numerous experimental advantages for drug discovery including genetic and molecular tractability, amenability to high-throughput screening methods and reduced experimental costs and increased experimental throughput compared to traditional mammalian models. ... This review will provide an overview of C. elegans, Drosophila, and zebrafish biology and husbandry and will discuss how these models are being used for phenotype-based drug screening and for identification of drug targets and mechanisms of action. ..."

Wednesday, January 11, 2017

Modified fly cultured cells as a biotherapeutic? Study suggests this could one day be an effective approach

Roy DG, Power AT, Bourgeois-Daigneault MC, Falls T, Ferreira L, Stern A, Tanese de Souza C, McCart JA, Stojdl DF, Lichty BD, Atkins H, Auer RC, Bell JC, Le Boeuf F. Programmable insect cell carriers for systemic delivery of integrated cancer biotherapy. J Control Release. 2015 Dec 28;220(Pt A):210-21. PMID: 26482080.

From the abstract: "Due to cancer's genetic complexity, significant advances in the treatment of metastatic disease will require sophisticated, multi-pronged therapeutic approaches. Here we demonstrate the utility of a Drosophila melanogaster cell platform for the production and in vivo delivery of multi-gene biotherapeutic systems. We show that cultured Drosophila S2 cell carriers can stably propagate oncolytic viral therapeutics that are highly cytotoxic for mammalian cancer cells without adverse effects on insect cell viability or gene expression. Drosophila cell carriers administered systemically to immunocompetent animals trafficked to tumors to deliver multiple biotherapeutics with little apparent off-target tissue homing or toxicity, resulting in a therapeutic effect. ..."

Monday, January 9, 2017

Journal issue focuses on fly models of disease

A special issue of Current Topics in Developmental Biology (vol. 121, January 2017) focuses on fly models of human diseases. Check out the journal issue titles to see what specific diseases and disorders are discussed in these expert-level review articles.