biostudies-literatureUnknown300(5)Pokrishevsky EALS Society of CanadaR Howard Webster FoundationProMIS Neurosciences IncAmyotrophic 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 WT TAR DNA-binding protein 43 (TDP-43). We show here that co-expression of mutant or WT TDP-43 with SOD1 leads to misfolding of endogenous SOD1 and aggregation of SOD1 reporter protein SOD1^G85R-GFP in human cell cultures and promotes synergistic axonopathy in zebrafish. Intriguingly, this pathological interaction is modulated by natively solvent-exposed tryptophans in SOD1 (tryptophan-32) and TDP-43 RNA-recognition motif RRM1 (tryptophan-172), in concert with natively sequestered TDP-43 N-terminal domain tryptopThe Journal of biological chemistry107207https://www.ebi.ac.uk/biostudies/studies/S-EPMC11087967biostudies-literatureTryptophan residues in TDP-43 and SOD1 modulate the cross-seeding and toxicity of SOD1.PMC11087967Pozzi SCashman NRJulien JPMcAlary LDijkstra ADuVal MGRoman APlotkin SSPokrishevsky ELouadi SAllison WTfalseTryptophan residues in TDP-43 and SOD1 modulate the cross-seeding and toxicity of SOD1.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 WT TAR DNA-binding protein 43 (TDP-43). We show here that co-expression of mutant or WT TDP-43 with SOD1 leads to misfolding of endogenous SOD1 and aggregation of SOD1 reporter protein SOD1^G85R-GFP in human cell cultures and promotes synergistic axonopathy in zebrafish. Intriguingly, this pathological interaction is modulated by natively solvent-exposed tryptophans in SOD1 (tryptophan-32) and TDP-43 RNA-recognition motif RRM1 (tryptophan-172), in concert with natively sequestered TDP-43 N-terminal domain tryptop2024-01-01T00:00:00Z2024 May2026-06-02T09:01:30.852Z2026-04-16T03:13:12.719ZS-EPMC110879673852251410.1016/j.jbc.2024.107207