Proceedings of the National Academy of Sciences of the United States of AmericaMar 11, 2021

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

Regenerative Health Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 25, 2026

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.

Simplified

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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Funding

Competing interests

Competing interest statement: G.W.Y. is a cofounder of Locana and Eclipse Bioinnovations and a member of the scientific advisory boards of Locana, Eclipse Bioinnovations, and Aquinnah Pharmaceuticals. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies. S.A.L. is a scientific cofounder of Adamas Pharmaceuticals, Inc. and EuMentis Therapeutics, Inc., as disclosed to the institutions with which he is academically affiliated and performs research in accordance with their conflict of interest policies.

PubMed

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

Abstract

Full Text

Funding

Competing interests

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