S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD

Mar 11, 2021Proceedings of the National Academy of Sciences of the United States of America

Modified TDP-43 protein causes clumps, spreads between cells, and nerve cell damage in stem cell and animal models of ALS and FTD

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Abstract

Nitrosative stress may trigger protein aggregation and cell-to-cell spread in neurodegenerative disorders.

Environmental factors can induce protein misfolding and aggregation through nitrosative stress.
In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), TDP-43 protein aggregation is a significant pathological feature.
Reactive nitrogen species lead to the formation of a modified version of TDP-43 (SNO-TDP-43), which promotes its aggregation.
Elevated levels of SNO-TDP-43 are observed in both postmortem human brains and in cell models of FTD/ALS.
Aggregated TDP-43 may exacerbate nitrosative stress, creating a cycle that leads to further aggregation and neuronal damage.

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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.

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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

Abstract

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