# S-Nitrosylation-Dependent Pathological Spread of Abnormal Proteins in Frontotemporal Dementia and Lewy Body Dementia

> **NIH NIH RF1** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $2,081,944

## Abstract

Aggregation and cell-to-cell spread of misfolded proteins are hallmarks of a variety of neurodegenerative
diseases, leading to cellular dysfunction, synaptic damage, and neuronal loss. Cell-to-cell propagation of TDP-
43, α-synuclein (α-syn), and tau aggregates is thought to contribute to disease progression in Alzheimer’s
disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD), and other neurodegenerative
diseases. Moreover, mounting evidence suggests that these proteinopathies often co-exist in the same
patients to various degrees. Hence, understanding how these pathological proteins spread throughout the
nervous system will open up new avenues for diagnostics and more effective therapeutics for these disorders.
In patients with dementia, synaptic loss and neuronal damage result in part from excessive generation of
reactive oxygen and nitrogen species (ROS/RNS) that is triggered by aggregated proteins. In fact, our group
has extensively shown that misfolded protein-induced RNS, such as nitric oxide (NO), contribute to synaptic
damage in models of LBD, AD and FTD via aberrant protein S-nitrosylation (forming SNO-proteins).
Intriguingly, we recently discovered that S-nitrosylation of TDP-43 and p62 promotes cell-to-cell transmission of
TDP-43 and α-syn, respectively. We have found that both TDP-43 and p62 are highly S-nitrosylated in human
patient brains with dementia, as well as in hiPSC (human induced pluripotent stem cell) and mouse models of
FTD and LBD compared to controls. Concerning SNO-TDP-43, we found that S-nitrosylation contributes to
aggregation of TDP-43 via oxidation-mediated disulfide-linkage; this process contributes to altered RNA-
binding activity and neurotoxicity in both cell-based and transgenic mouse models of TDP-43 proteinopathy.
Moreover, we found enhanced spreading of aggregated TDP-43 protein triggered by RNS-mediated oxidation,
as seen in FTD. Concerning SNO-p62, we found that S-nitrosylation of the adaptor protein p62 inhibits
autophagic flux, leading to intracellular build-up and consequent secretion of misfolded α-syn via both direct
release and secretion of extracellular vesicles. In the current application, we demonstrate redox-dependent
spreading of abnormally aggregated proteins in hiPSC models (2D cultures and 3D brain organoids) and
mouse models of FTD and LBD. We use these models to show (i) seeding with S-nitrosylated/oxidized TDP-43
promotes TDP-43 spreading and TDP-43 proteinopathy, (ii) SNO-p62 formation promotes α-syn spreading and
neurotoxicity, and (iii) aberrant SNO-p62 and SNO-TDP-43 pathways interact to enhance TDP-43 and α-syn
spreading.

## Key facts

- **NIH application ID:** 10291048
- **Project number:** 1RF1NS123298-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Tomohiro Nakamura
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,081,944
- **Award type:** 1
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10291048

## Citation

> US National Institutes of Health, RePORTER application 10291048, S-Nitrosylation-Dependent Pathological Spread of Abnormal Proteins in Frontotemporal Dementia and Lewy Body Dementia (1RF1NS123298-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10291048. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*