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S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD
- Source :
- Proc Natl Acad Sci U S A
- Publication Year :
- 2021
- Publisher :
- Proceedings of the National Academy of Sciences, 2021.
-
Abstract
- Rare genetic mutations result in aggregation and spreading of cognate proteins in neurodegenerative disorders; however, in the absence of mutation (i.e., in the vast majority of “sporadic” cases), mechanisms for protein misfolding/aggregation remain largely unknown. Here, we show environmentally induced nitrosative stress triggers protein aggregation and cell-to-cell spread. In patient brains with amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), aggregation of the RNA-binding protein TDP-43 constitutes a major component of aberrant cytoplasmic inclusions. We identify a pathological signaling cascade whereby reactive nitrogen species cause S-nitrosylation of TDP-43 (forming SNO-TDP-43) to facilitate disulfide linkage and consequent TDP-43 aggregation. Similar pathological SNO-TDP-43 levels occur in postmortem human FTD/ALS brains and in cell-based models, including human-induced pluripotent stem cell (hiPSC)-derived neurons. Aggregated TDP-43 triggers additional nitrosative stress, representing positive feed forward leading to further SNO-TDP-43 formation and disulfide-linked oligomerization/aggregation. Critically, we show that these redox reactions facilitate cell spreading in vivo and interfere with the TDP-43 RNA-binding activity, affecting SNMT1 and phospho-(p)CREB levels, thus contributing to neuronal damage in ALS/FTD disorders.
- Subjects :
- Induced Pluripotent Stem Cells
Cell
Protein aggregation
Biology
Nitric Oxide
medicine.disease_cause
CREB
Protein Aggregation, Pathological
Stress, Physiological
mental disorders
medicine
Humans
Cysteine
RNA Processing, Post-Transcriptional
Amyotrophic lateral sclerosis
Induced pluripotent stem cell
Motor Neurons
Mutation
S-Nitrosothiols
Multidisciplinary
Amyotrophic Lateral Sclerosis
Neurotoxicity
Brain
nutritional and metabolic diseases
S-Nitrosylation
Biological Sciences
medicine.disease
Reactive Nitrogen Species
nervous system diseases
Cell biology
DNA-Binding Proteins
medicine.anatomical_structure
Frontotemporal Dementia
biology.protein
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 118
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....a1b8306a5c570747fd63e7d61865e592