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Tryptophan residues in TDP-43 and SOD1 mediate the cross-seeding and toxicity of SOD1

By Edward Pokrishevsky, Michèle G. DuVal, McAlary L., Sarah Louadi, Silvia Pozzi, Andrei Roman, Steven S Plotkin, Anke Dijkstra, Jean-Pierre Julien, W. Ted Allison, Neil R. Cashman

Posted 28 Jul 2020
bioRxiv DOI: 10.1101/2020.07.27.224188

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. ### Competing Interest Statement JPJ and SP are owners of a patent US 15/532,909 titled [TDP-43-binding polypeptides useful for the treatment of neurodegenerative diseases]. JPJ is chief scientific officer of Imstar Therapeutics. The 3H1 misfolded SOD1 antibody used in this manuscript is owned by the University of British Columbia, and licensed by ProMIS Neurosciences. NRC and SSP are Chief Scientific Officer and Chief Physics Officer 18 of ProMIS Neurosciences, respectively. SSP and NRC have received consultation compensation from ProMIS, and possess ProMIS stock and stock options.

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