TDP-43 aggregation induced by oxidative stress causes global mitochondrial imbalance in ALS.
Amyotrophic Lateral Sclerosis
/ metabolism
Animals
Cell Line
DNA-Binding Proteins
/ metabolism
Embryo, Mammalian
Humans
Mice
Mice, Inbred C57BL
Mitochondria
/ metabolism
Mitochondrial Proteins
/ metabolism
Neurons
/ metabolism
Oxidative Stress
Protein Aggregates
Protein Aggregation, Pathological
Reactive Oxygen Species
/ metabolism
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
20
11
2019
accepted:
06
11
2020
pubmed:
6
1
2021
medline:
1
4
2021
entrez:
5
1
2021
Statut:
ppublish
Résumé
Amyotrophic lateral sclerosis (ALS) was initially thought to be associated with oxidative stress when it was first linked to mutant superoxide dismutase 1 (SOD1). The subsequent discovery of ALS-linked genes functioning in RNA processing and proteostasis raised the question of how different biological pathways converge to cause the disease. Both familial and sporadic ALS are characterized by the aggregation of the essential DNA- and RNA-binding protein TDP-43, suggesting a central role in ALS etiology. Here we report that TDP-43 aggregation in neuronal cells of mouse and human origin causes sensitivity to oxidative stress. Aggregated TDP-43 sequesters specific microRNAs (miRNAs) and proteins, leading to increased levels of some proteins while functionally depleting others. Many of those functionally perturbed gene products are nuclear-genome-encoded mitochondrial proteins, and their dysregulation causes a global mitochondrial imbalance that augments oxidative stress. We propose that this stress-aggregation cycle may underlie ALS onset and progression.
Identifiants
pubmed: 33398173
doi: 10.1038/s41594-020-00537-7
pii: 10.1038/s41594-020-00537-7
doi:
Substances chimiques
DNA-Binding Proteins
0
Mitochondrial Proteins
0
Protein Aggregates
0
Reactive Oxygen Species
0
TARDBP protein, human
0
TDP-43 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
132-142Références
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