Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.27.224188v1?rss=1 Authors: Pokrishevsky, E., Duval, M. G., McAlary, L., Louadi, S., Pozzi, S., Roman, A. Y., Plotkin, S. S., Dijkstra, A., Julien, J.-P., Allison, W. T., Cashman, N. R. Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons. Neuronal superoxide dismutase-1 (SOD1) inclusion bodies are characteristic of familial ALS with SOD1 mutations, while a hallmark of sporadic ALS is inclusions containing aggregated wild-type TAR DNA-binding protein 43 (TDP-43). Co-expression of mutant or wild-type TDP-43 with SOD1 leads to misfolding of endogenous SOD1 and aggregation of SOD1 reporter protein G85R-GFP in HEK293FT cells, and promotes synergistic axonopathy in zebrafish. This pathological interaction is dependent upon natively solvent-exposed tryptophans in SOD1 (tryptophan-32) and TDP-43 RRM1 (tryptophan-172), in concert with natively sequestered TDP-43 N-terminal domain tryptophan-68. TDP-43 RRM1 intrabodies reduce wild-type SOD1 misfolding in HEK293FT cells, via blocking tryptophan-172. Tryptophan-68 becomes antibody-accessible in aggregated TDP-43 in sporadic ALS motor neurons and cell culture. 5-fluorouridine inhibits TDP-43-induced G85R-GFP SOD1 aggregation in HEK293FT cells, and ameliorates axonopathy in zebrafish, via its interaction with SOD1 tryptophan-32. Collectively, our results establish a novel and potentially druggable tryptophan-mediated mechanism whereby two principal ALS disease effector proteins might directly interact in disease. Copy rights belong to original authors. Visit the link for more info