# An optogenetic approach to establish the interplay between stress granules and TDP-43 proteinopathy in ALS/FTD

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $372,719

## Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder marked
by loss of motor neurons of the spinal cord and cortex. ALS is characterized by significant
heterogeneity in disease onset and patient presentation. Over the last twenty years, mutations
in over 35 different genes have been uncovered as causal in the development of familial forms
of ALS (fALS); however, fALS only accounts for roughly 10% of all ALS cases. The remaining
90% of patients suffer from sporadic ALS (sALS), with no family history of disease and unknown
causes of pathogenesis. Regardless of all this genetic and pathogenic complexity, remarkably
nearly every single ALS patient (both fALS and sALS) share a common neuropathology in the
form of aberrant cytoplasmic inclusions of a protein called TAR DNA-binding protein of 43 kDa
(TDP-43) found in degenerating regions of the nervous system. Insight drawn from studies of
fALS-linked mutations have implicated stress granule dysfunction in disease development, but
the exact mechanisms by which the stress granules may directly regulate TDP-43 aggregation
remains unclear. By utilizing a novel optogenetic approach to induce either TDP-43 inclusions or
functional stress granules, we can manipulate these processes at a previously unattainable
level of control. These experiments will explore the contribution of stress granule dysfunction to
TDP-43 inclusion neurotoxicity. We hypothesize that perturbations in stress granule dynamics
contribute to neurotoxic TDP-43 aggregation in ALS. We will first investigate the contribution of
stress granules to light-induced TDP-43 inclusions. We will then determine if chronic or
persistent stress granule formation initiates TDP-43 proteinopathy. Finally, we will perform a
genome-wide RNAi screen to identify novel pathways that protect against TDP-43 inclusion
toxicity and assess whether this protection is dependent on stress granule regulation.

## Key facts

- **NIH application ID:** 10133164
- **Project number:** 5R01NS105756-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Christopher James Donnelly
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $372,719
- **Award type:** 5
- **Project period:** 2018-03-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133164

## Citation

> US National Institutes of Health, RePORTER application 10133164, An optogenetic approach to establish the interplay between stress granules and TDP-43 proteinopathy in ALS/FTD (5R01NS105756-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133164. Licensed CC0.

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