Investigating interactions of TDP-43 with the insulin pathway in a Drosophila model of amyotrophic lateral sclerosis. Andrés A Morera¹, Taylor Podolsky¹, Alyssa Coyne², Archi Joardar¹, Daniela Zarnescu^1,3. 1) Department of Molecular and Cell Biology, University of Arizona, Tucson, AZ; 2) Department of Neuroscience, University of Arizona, Tucson, AZ; 3) Department of Neurology, University of Arizona, Tucson, AZ.

   ALS is a devastating adult-onset neurodegenerative disease that causes progressive muscle atrophy due to degeneration of upper and lower motor neurons, leading to paralysis and death within 2 - 5 years of onset of clinical symptoms. TDP-43, a ubiquitously expressed RNA binding protein, was found to be a common component of intraneuronal inclusions in motor neurons of ALS cases, as well as in other neurodegenerative diseases. We have developed a Drosophila model of ALS based on TDP-43, which recapitulates many features of the human disease, including locomotor defects, neuromuscular junction defects, motor neuron degeneration, and increased mortality. Using a combination of genetic and drug screening approaches we found that TDP-43 overexpression in motor neurons impacts the insulin/Pi3K/Akt/TOR signaling cassette. This led us to hypothesize that insulin signaling is dysregulated in our ALS model based on TDP-43. Current experiments are aimed at identifying and characterizing components of the insulin/PI3K/Akt/TOR signaling cassette that may mediate TDP-43s neurotoxicity. To accomplish this, we use the Gal4-UAS system to manipulate expression of insulin pathway components in the context of TDP-43 overexpression in various Drosophila tissues including photoreceptors, motor neurons or glia. By observing the effects of these manipulations on the TDP-43 neurodegenerative phenotype, we can better understand the physiological role of TDP-43 and dissect the mechanisms by which TDP-43 and components of the insulin pathway may lead to neurotoxicity in ALS and other neurodegenerative diseases.