1. S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD
- Author
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Pirie, Elaine, Oh, Chang-Ki, Zhang, Xu, Han, Xuemei, Cieplak, Piotr, Scott, Henry R, Deal, Amanda K, Ghatak, Swagata, Martinez, Fernando J, Yeo, Gene W, Yates, John R, Nakamura, Tomohiro, and Lipton, Stuart A
- Subjects
ALS ,Stem Cell Research ,Neurosciences ,Dementia ,Acquired Cognitive Impairment ,Frontotemporal Dementia (FTD) ,Neurodegenerative ,Rare Diseases ,Brain Disorders ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Amyotrophic Lateral Sclerosis ,Brain ,Cysteine ,DNA-Binding Proteins ,Frontotemporal Dementia ,Humans ,Induced Pluripotent Stem Cells ,Motor Neurons ,Nitric Oxide ,Protein Aggregation ,Pathological ,RNA Processing ,Post-Transcriptional ,Reactive Nitrogen Species ,S-Nitrosothiols ,Stress ,Physiological ,TDP-43 proteinopathy ,S-nitrosylation ,aggregation ,spread - 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.
- Published
- 2021