title: Network analyses reveal novel aspects of ALS pathogenesis.
abstract: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of motor neurons, muscle atrophy and paralysis. Mutations in the human VAMP-associated protein B (hVAPB) cause a heterogeneous group of motor neuron diseases including ALS8. Despite extensive research, the molecular mechanisms underlying ALS pathogenesis remain largely unknown. Genetic screens for key interactors of hVAPB activity in the intact nervous system, however, represent a fundamental approach towards understanding the in vivo function of hVAPB and its role in ALS pathogenesis. Targeted expression of the disease-causing allele leads to neurodegeneration and progressive decline in motor performance when expressed in the adult Drosophila, eye or in its entire nervous system, respectively. By using these two phenotypic readouts, we carried out a systematic survey of the Drosophila genome to identify modifiers of hVAPB-induced neurotoxicity. Modifiers cluster in a diverse array of biological functions including processes and genes that have been previously linked to hVAPB function, such as proteolysis and vesicular trafficking. In addition to established mechanisms, the screen identified endocytic trafficking and genes controlling proliferation and apoptosis as potent modifiers of ALS8-mediated defects. Surprisingly, the list of modifiers was mostly enriched for proteins linked to lipid droplet biogenesis and dynamics. Computational analysis reveals that most modifiers can be linked into a complex network of interacting genes, and that the human genes homologous to the Drosophila modifiers can be assembled into an interacting network largely overlapping with that in flies. Identity markers of the endocytic process were also found to abnormally accumulate in ALS patients, further supporting the relevance of the fly data for human biology. Collectively, these results not only lead to a better understanding of hVAPB function but also point to potentially relevant targets for therapeutic intervention.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom; Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Mario
authors.initials: M
authors.lastname: Sanhueza
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom; Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, United Kingdom; Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Houston, Texas, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Chai
authors.affiliation: Academic Department of Neuropathology, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Colin
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America.
authors.forename: Brett A
authors.initials: BA
authors.lastname: McCray
authors.affiliation: Biomathematics and Statistics Scotland, University of Edinburgh, United Kingdom; Institute for Adaptive and Neural Computation, School of Informatics, University of Edinburgh, United Kingdom.
authors.forename: T Ian
authors.initials: TI
authors.lastname: Simpson
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom; Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Giuseppa
authors.initials: G
authors.lastname: Pennetta
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001344:Autopsy; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D049750:Genome, Insect; D006801:Humans; D066292:Lipid Droplets / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D060066:Protein Interaction Maps / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics; D059748:Proteolysis; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D029721:Drosophila Proteins; D008565:Membrane Proteins; C496748:VAPB protein, human; C491921:Vap33 protein, Drosophila; D033921:Vesicular Transport Proteins
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