PUBLICATION
Tryptophan residues in TDP-43 and SOD1 modulate the cross-seeding and toxicity of SOD1
- Authors
- Pokrishevsky, E., DuVal, M.G., McAlary, L., Louadi, S., Pozzi, S., Roman, A., Plotkin, S.S., Dijkstra, A., Julien, J.P., Allison, W.T., Cashman, N.R.
- ID
- ZDB-PUB-240325-4
- Date
- 2024
- Source
- The Journal of biological chemistry 300(5): 107207 (Journal)
- Registered Authors
- Allison, Ted, Duval, Michèle
- Keywords
- none
- MeSH Terms
-
- Amyotrophic Lateral Sclerosis*/genetics
- Amyotrophic Lateral Sclerosis*/metabolism
- Amyotrophic Lateral Sclerosis*/pathology
- Animals
- DNA-Binding Proteins*/genetics
- DNA-Binding Proteins*/metabolism
- Humans
- Motor Neurons/metabolism
- Motor Neurons/pathology
- Protein Folding
- Superoxide Dismutase-1*/chemistry
- Superoxide Dismutase-1*/genetics
- Superoxide Dismutase-1*/metabolism
- Tryptophan*/metabolism
- Zebrafish*
- PubMed
- 38522514 Full text @ J. Biol. Chem.
Citation
Pokrishevsky, E., DuVal, M.G., McAlary, L., Louadi, S., Pozzi, S., Roman, A., Plotkin, S.S., Dijkstra, A., Julien, J.P., Allison, W.T., Cashman, N.R. (2024) Tryptophan residues in TDP-43 and SOD1 modulate the cross-seeding and toxicity of SOD1. The Journal of biological chemistry. 300(5):107207.
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). We show here that co-expression of mutant or wild-type TDP-43 with SOD1 leads to misfolding of endogenous SOD1 and aggregation of SOD1 reporter protein SOD1G85R-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 wild-type 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping