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Tryptophan residues in TDP-43 and SOD1 modulate the cross-seeding and toxicity of SOD1.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2024 May; Vol. 300 (5), pp. 107207. Date of Electronic Publication: 2024 Mar 22. - Publication Year :
- 2024
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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 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 <superscript>G85R</superscript> -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 tryptophan-68. TDP-43 RRM1 intrabodies reduce WT SOD1 misfolding in human cell cultures, 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 human cell cultures 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.<br />Competing Interests: Conflict of interest J.-P. J. and S. P. are the owners of a patent US 15/532,909 titled “TDP-43-binding polypeptides useful for the treatment of neurodegenerative diseases”. J.-P. J. is the 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. N. R. C. is the Chief Scientific Officer of ProMIS Neurosciences. S. S. P. and N. R. C. have received consultation compensation from ProMIS and possess ProMIS stock and stock options. All other authors declare that they have no conflicts of interest with the contents of this article.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Animals
Protein Folding
Motor Neurons metabolism
Motor Neurons pathology
Tryptophan metabolism
Zebrafish
Superoxide Dismutase-1 metabolism
Superoxide Dismutase-1 genetics
Superoxide Dismutase-1 chemistry
DNA-Binding Proteins metabolism
DNA-Binding Proteins genetics
Amyotrophic Lateral Sclerosis metabolism
Amyotrophic Lateral Sclerosis genetics
Amyotrophic Lateral Sclerosis pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 300
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38522514
- Full Text :
- https://doi.org/10.1016/j.jbc.2024.107207