# TDP-43 acetylation, phase separation, aggregation, and clearance by antibody-mediated degradation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $759,191

## Abstract

Cytoplasmic aggregation of TDP-43 has been reported in almost every age-dependent neurodegenerative
disease, including in >40% of frontal temporal dementia (FTD), in the hippocampal neurons of Alzheimer's
disease (AD) patients, in >90% of ALS, and in ~100% of a recently recognized AD-like dementia in the oldest
of the elderly, an AD-like syndrome identified in 2019 and named Limbic-predominant Age-related TDP-43
Encephalopathy (LATE). We have demonstrated that TDP-43 phase separation and aggregation can drive
neuronal death independent of RNA binding, stress granule formation, and TDP-43 association with stress
granules. We have subsequently identified that acetylation of TDP-43 (which abolishes its RNA binding)
drives its separation into liquid spherical annular bodies. These nuclear annuli have liquid annular shells
enriched in TDP-43 and liquid centers highly enriched in HSP70 family molecular chaperones. Use of
inhibitors of known deacetylases or the proteasome (to mimic the known age-dependent declines in deacetylase
and proteasome activities) provokes cytoplasmic TDP-43 aggregation. We propose to determine the biological
and pathological role(s) of acetylated TDP-43 and how HSP70 chaperone activity regulates nuclear TDP-43
function and its aggregation in the cytoplasm. We will determine the regulation and biological consequences of
acetylated TDP-43 in neurons by identifying the key regulatory enzymes (acetyltranferases and deacetylases)
of acetylated TDP-43 and alter TDP-43’s function in RNA splicing and its subcellular localization/aggregation.
To understand how HSP70 family molecular chaperones regulates phase transition of TDP-43, we will use Hsc70
(encoded by the HSPA8 gene and the most abundant HSP70 in neurons) and determine how Hsc70 interacts
with TDP-43. We will also determine if enhancing the activity of HSP70 (such as HSPA8, which is highly
expressed in neurons) ameliorates TDP-43 pathology. We will also develop a potential therapeutic approach for
TDP-43 proteinopathies in which rapid proteasome-mediated degradation of aggregated TDP-43 is achieved
through an engineered E3 ubiquitin ligase linked to a synthetically evolved nanobody (a single chain
antibody derived from an antibody heavy chain) recognizing either acetylated or phosphorylated TDP-43.
Outcomes of these efforts will provide key insights for understanding basic aspects of TDP-43 biology and
pathobiology in common dementia, and for developing a new concept of therapy that specifically targets TDP-
43 pathology that could potentially benefit aged patients with TDP-43-related dementia.

## Key facts

- **NIH application ID:** 10184466
- **Project number:** 1R01NS121604-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** GEOFFREY A CHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $759,191
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10184466

## Citation

> US National Institutes of Health, RePORTER application 10184466, TDP-43 acetylation, phase separation, aggregation, and clearance by antibody-mediated degradation (1R01NS121604-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10184466. Licensed CC0.

---

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