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."