# Disease Mechanism and Therapy in TDP-43 Proteinopathies and Dementias

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $768,106

## Abstract

Nuclear clearance and cytoplasmic aggregation of TDP-43 have been reported in almost every age-dependent
neurodegenerative disease, including as the defining feature of a recently recognized dementia in the oldest of
the elderly, an AD-like syndrome named Limbic-predominant Age-related TDP-43 Encephalopathy (LATE), a
proportion of the hippocampal neurons in Alzheimer's disease (AD), >40% of frontal temporal dementia
(FTD), and >90% of instances of ALS. Our prior efforts (for which we now seek renewed support) have
established that transient stress can induce Liquid-Liquid Phase Separation (LLPS) of cytoplasmic TDP-43 into
liquid droplets that then transition to a solid state, slowly deplete nuclear TDP-43, and provoke cell death over a
timescale of weeks. We also determined that partial or complete proteasome inhibition (to mimic the established
decline in proteosome activity during normal aging) provokes TDP-43 mislocalization/accumulation within the
cytoplasm. Quantitative mass spectrometry (with proximity-labeling and isobaric-tagging) has identified the small
heat shock protein HSPB1 to be a regulator of cytoplasmic TDP-43 phase separation and subsequent
aggregation. HSPB1 partitions into TDP-43 droplets, inhibits TDP-43 assembly into fibrils, and mediates
disassembly of stress-induced, TDP-43 droplets. Building on our prior and continuing work, we now propose to
determine 1) how the age-dependent decrease in proteasome activity drives TDP-43 loss of function,
cytoplasmic mislocalization, phase separation, and aggregation and 2) how protein chaperone HSPB1, in
conjunction with HSP70, affects cytoplasmic TDP-43 phase separation, inhibits TDP-43 assembly into fibrils,
and mediates disassembly of TDP-43 droplets. We have also initiated development of an approach to generate
new/replacement neurons in the aged adult mouse brain by transiently suppressing the RNA binding protein
Polypyrimidine Tract Binding Protein-1 (PTB) using an antisense oligonucleotide (ASO) delivered by a
single injection into cerebral spinal fluid (CSF). Radial glial-like cells (and possibly other GFAP-expressing
cells) convert into new neurons over a two month period, acquire mature neuronal character, and functionally
integrate into endogenous circuits that modify mouse behavior. Here we will systematically identify the
functionality, localization, cell origin, timing, and molecular pathways of cells undergoing identity conversion, with
a primary assay the development and utilization of single cell RNA signatures obtained with spatial
transcriptomics (Multiplexed Error-Robust Fluorescence In Situ Hybridization [MERFISH]).

## Key facts

- **NIH application ID:** 10906332
- **Project number:** 5R01NS027036-37
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Bogdan Bintu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $768,106
- **Award type:** 5
- **Project period:** 1989-04-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906332

## Citation

> US National Institutes of Health, RePORTER application 10906332, Disease Mechanism and Therapy in TDP-43 Proteinopathies and Dementias (5R01NS027036-37). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10906332. Licensed CC0.

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