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."