Elucidating the Role of TDP-43 in the Pathogenesis of Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease with no cure. TAR-DNA binding protein 43 (TDP-43) is the major component of the cytoplasmic inclusions characteristic of ALS. Transgenic Drosophila lines expressing wild-type, mutant and splice variants of human TDP-43 were generated. I find that ubiquitous expression of all TDP-43 transgenes, except for TDP-43∆C-term, is sufficient to cause lethality. I also show that eye-specific expression of a TDP-43∆N-term splice variant, which localizes diffusely to the cytosol, results in increased cell toxicity suggesting an association between cytosolic localization and toxicity. Consistent with this model, I find that the TDP-43∆N-term splice variant is capable of recruiting full length TDP-43 into the cytoplasm, and I suggest this may represent an initiating event in TDP-43-linked ALS. Altogether, my results seem to indicate that exclusion of TDP-43 from the nucleus rather than its presence in aggregates is linked to increased cytotoxicity and lethality in ALS.MAS