title: Insights into ALS pathomechanisms: from flies to humans.
abstract: Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease causing the death of motor neurons with consequent muscle atrophy and paralysis. Several neurodegenerative diseases have been modeled in Drosophila and genetic studies on this model organism led to the elucidation of crucial aspects of disease mechanisms. ALS, however, has lagged somewhat behind possibly because of the lack of a suitable genetic model. We were the first to develop a fly model for ALS and over the last few years, we have implemented and used this model for a large scale, unbiased modifier screen. We also report an extensive bioinformatic analysis of the genetic modifiers and we show that most of them are associated in a network of interacting genes controlling known as well as novel cellular processes involved in ALS pathogenesis. A similar analysis for the human homologues of the Drosophila modifiers and the validation of a subset of them in human tissues confirm and expand the significance of the data for the human disease. Finally, we analyze a possible application of the model in the process of therapeutic discovery in ALS and we discuss the importance of novel "non-obvious" models for the disease.
authors.affiliation: a Euan McDonald Center for Motor Neurone Disease Research.|b Centre for Integrative Physiology; University of Edinburgh ; Edinburgh ; UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Chai
authors.affiliation: a Euan McDonald Center for Motor Neurone Disease Research.|b Centre for Integrative Physiology; University of Edinburgh ; Edinburgh ; UK.
authors.forename: Giuseppa
authors.initials: G
authors.lastname: Pennetta
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002490:Central Nervous System / Q000502:physiology*; D019295:Computational Biology; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*
keywords: Amyotrophic Lateral Sclerosis; Drosophila model; VAMP-Associated Protein B; cell proliferation/apoptosis; computational analysis; endocytosis; human tissue validation; large scale modifier screen; lipid droplets