[
International Worm Meeting,
2015]
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders (autism, Asperger syndrome and persuasive development disorders) resulting in limited social interactions, repetitive and restricted behavior and a delay in cognitive development and language. The prevalence of ASD is increasing and there are no pharmacological therapies available that successfully treat core ASD deficits. Therefore, the development of novel therapeutics for ASD is urgently needed. To identify genes that are linked to ASD in humans, we used the SFARI Gene Scoring Module of the Simons Foundation Autism Research Initiative. This tool includes an evolving database that is centered on genes implicated in ASD susceptibility. It integrates different kinds of genetic data that are being generated by contributing researchers. Based on this system, we selected 27 genes that have orthologs in C. elegans and viable loss-of-function (LOF) mutants. These LOF mutants were screened for motor-deficiency phenotypes using an automated worm tracking apparatus to automatically measure swimming activity (swimming movements) of C.elegans strains. From the 27 genes tested, 11 LOF mutants showed a pronounced motor-deficient phenotype amenable for screening applications.Subsequently, 4 neuroprotective compounds (methylene blue, pimozide, salubrinal, guanabenz) previously identified in our lab were tested for their ability to rescue the motor-deficient phenotypes in these 11 LOF mutants. The promising results of this pre-screen, i.e. the correction of the motor-deficient phenotype into a wild type-like motility, prompted us to expand our approach perform a comprehensive, blind drug screen of ~3600 FDA approved compounds for several LOF mutants. The aim of this screen is to identify new compounds that allow us to directly gain insights into the mechanisms underlying neuronal dysfunction and ASD.ASD are complex and multifactorial neurodevelopmental disorders. Using C. elegans to study genes implicated in ASD in conjunction with well-characterized, FDA-approved compounds may identify underlying mechanisms that could be used to develop novel therapeutic approaches. .
[
International Worm Meeting,
2017]
Polyglutamine expansion diseases are a class of dominantly inherited neurodegenerative disorders that develop when a CAG repeat in the causative genes is unstably expanded above a certain threshold. The expansion of trinucleotide CAG repeats causes hereditary adult-onset neurodegenerative disorders such as multiple forms of spinocerebellar ataxia (SCA). The most common dominantly inherited spinocerebellar ataxia is the type 3 (SCA3) also known as Machado-Joseph disease (MJD), an autosomal dominant, progressive neurological disorder. The gene causing MJD is ATXN3 (ATAXIN-3). The prevalence of MJD is increasing and there are no pharmacological therapies available that successfully treat this disease. Therefore, the development of novel therapeutics for MJD is urgently needed. In this study, we generated transgenic C. elegans strains expressing wild type or mutant human ATXN3 genes and tested them for recovery of motility defects, decreased lifespan, and neurodegeneration phenotypes upon treatment with compounds known to modulate ER stress and having neuroprotective roles. We observed differences between both transgenic lines and found that the motility defects, the reduced lifespan and neurodegeneration were rescued by compounds that have been previously identified in our laboratory. These compounds were also able to prevent the oxidative stress and the ER stress response induced by mutant ATXN3 in transgenic worms. These promising results prompted us to expand our approach perform to a comprehensive, blind drug screen of ~3600 compounds in our transgenic ATXN3 lines. The aim of this screen is to identify new compounds that allow us to directly gain insights into the mechanisms underlying MJD. We introduce novel C. elegans models for MJD based on the expression of full-length ATXN3 in GABAergic motor neurons. Using these models we discovered that chemical modulation of the ER unfolded protein response reduced neurodegeneration and could be a new therapeutic approach for the treatment of MJD. Also, using C. elegans to study MJD in conjunction with well-characterized compounds, we may identify underlying mechanisms that could also be used to develop novel therapeutic approaches.