# Deubiquitinase USP19 in TDP-43 pathogenesis.

> **NIH NIH RF1** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $1,785,220

## Abstract

The RNA-binding nuclear protein TDP-43 mislocalizes to the cytoplasm and aggregates in
Frontotemporal lobar degeneration (FTLD-TDP variant), Amyotrophic Lateral Sclerosis (ALS),
and >50% of late-onset Alzheimer’s disease (AD). Abnormal TDP-43 mislocalization and
accumulation is associated with endoplasmic reticulum (ER) stress, synaptic dysfunction, and
cognitive and motor impairments. While TDP-43 undergoes different post-translational
modifications including phosphorylation, poly ADP-ribosylation, oxidation, acetylation,
sumoylation, and ubiquitination, ubiquitination is a final key modification required for the turnover
of TDP-43 via the ubiquitin-proteasome system and autophagy-lysosome pathways. TDP-43 is
ubiquitinated by E3 ligases Parkin, PJA1, and Znf179. However, the role of deubiquitinases
(DUBs) in the regulation of TDP-43 function, turnover, proteinopathy, and toxicity is poorly
understood. The human genome encodes ~90 DUBs. Ubiquitin specific peptidases (USPs) are
the largest family of DUBs comprising ~50 members in humans. Of these, 27 are expressed in
the CNS. Our results from an unbiased screen of CNS-expressed DUBs identified USP19 as a
major TDP-43 DUB, a positive regulator of TDP-43 stability, and a promising candidate for further
study. Specifically, preliminary studies indicate that USP19, a DUB elevated during aging and in
brains of FTLD-TDP patients, acts to increase TDP-43 stability/aggregation and participates in
TDP-43-induced ER stress.
By taking advantage of mouse models and human postmortem tissues together with molecular,
cell biological, imaging, biochemical, proteomics, electrophysiological, behavioral, viral,
histochemical, and recombinant protein toolsets, this proposal will 1. validate the role of USP19
in TDP-43 pathogenesis and associated phenotypes vivo, and 2. determine the mechanistic basis
of USP19 in TDP-43 deubiquitination, stability, aggregation, and toxicity in genetically modified
neurons and in vitro systems.
Successful conclusion of these studies will determine the significant contribution of USP19 and
its DUB activity to TDP-43 pathogenesis in humans and mice. Moreover, these results will provide
novel mechanistic insights to USP19 DUB activity in concert with TDP-43 in ER stress and
neurotoxicity. Together, these studies will enable the pursuit of a potential therapeutic direction of
targeting USP19-mediated mechanisms to mitigate TDP-43 pathology and toxicity.

## Key facts

- **NIH application ID:** 10463231
- **Project number:** 1RF1NS122218-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** David E Kang
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,785,220
- **Award type:** 1
- **Project period:** 2022-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463231

## Citation

> US National Institutes of Health, RePORTER application 10463231, Deubiquitinase USP19 in TDP-43 pathogenesis. (1RF1NS122218-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10463231. Licensed CC0.

---

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