Transcription related proteins modify TDP-43 mediated toxicity in a fly model of ALS
Authors: Deepak Chhangani 1; Swapnil Pandey 1; Lorena de Mena 1; Pedro Fernandez-Funez 1; Diego Rincon Limas 1, 2
Affiliations: 1) Department of Neurology, University of Florida, Gainesville, FL; 2) Department of Neuroscience, University of Florida, Gainesville, FL
Keywords: a. neural degeneration; b. transcription initiation/elongation/termination
Tar DNA binding Protein-43 (TDP-43) is a major DNA/RNA binding protein involved in multiple cellular processes including transcriptional regulation, mRNA splicing and stress granules formation. Mutations in TDP-43, such as TDP-43M337V, cause Amyotrophic Lateral Sclerosis (ALS). Abnormal accumulation and phosphorylation of TDP-43 is also associated with Frontotemporal Dementia (FTD) and Alzheimer’s disease (AD). Despite its contributions to several devastating diseases, the toxic properties of TDP-43 are less understood, and hence, lesser is known about modifiers of its toxic effects. Here, we report the first genetic screen of over six thousand next generation RNAi lines in a Drosophila model expressing human TDP-43M337V. We found ~200 genetic modifiers of TDP-43 toxicity using a degenerative fly eye phenotype as screening platform. We discovered a large number of genes encoding various transcription factor and RNA polymerase subunits, as robust modifiers of the proteinopathy in Drosophila eye. We anticipate that modifying or altering these genes can suppress the toxic effects caused by pathological TDP-43 mammalian models and may lead to the development of potential therapeutic approaches against TDP-43 proteinopathies. This work was supported by NIH grant R01059871.