# Atypical TDP43 isoforrms driving neurodegeneration in FTD/ALS

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $390,000

## Abstract

Cytosolic mislocalization of the RNA binding protein TDP43 and neuronal hyperexcitability are cardinal
features of TDP43-related frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Nuclear
exclusion and cytosolic deposition of TDP43 are found in over half of those with FTD, and nearly 95% of those
with ALS, but the origin of these changes remains unknown. Likewise, neuronal hyperexcitability is a
ubiquitous finding in FTD/ALS patients, in vivo and in vitro disease models, yet the cause and consequences of
this phenomenon are unclear. Our preliminary data show for the first time an intrinsic connection between
TDP43 deposition and neuronal hyperexcitabilty that may play a pivotal part in the neurodegeneration
observed in TDP43-related FTD/ALS. Elevated neuronal activity upregulates an uncommon TDP43 isoform
that lacks the canonical, low-complexity carboxy-terminus of the protein. Due to its active nuclear export and its
ability to bind full-length (fl)TDP43, This shortened (s)TDP43 isoform is actively exported from the nucleus,
accumulates in cytosolic aggregates, and sequestrates full-length (fl)TDP43, thereby recapitulating TDP43
pathology in FTD/ALS. Our central goal with this project is to determine the impact of sTDP43 in FTD/ALS
pathogenesis, with a long-term objective of defining novel and effective therapeutic strategies targeting TDP43
homeostasis. We will test the hypothesis that sTDP43 drives neurodegeneration in TDP43-related FTD/ALS by
three specific aims. First, we will take advantage of an sTDP43-specific antibody that we developed to
determine the prevalence and distribution of sTDP43 accumulation in a large cohort of sporadic and familial
FTD/ALS cases curated by the University of Michigan Brain Bank. We will also investigate the impact of
sTDP43 on RNA homeostasis, and determine the relationship between sTDP43, stress, and stress granules in
disease models. Lastly, we will assess the contribution of sTDP43 to neurodegeneration in rodent primary
neurons and human induced pluripotent stem cell-derived neurons from patients carrying FTD/ALS-associated
C9orf72 hexanucleotide expansion mutations. At the completion of these studies, we will have delineated a
unique disease mechanism leading to neurodegeneration in TDP43-related FTD/ALS, and highlighted potential
therapeutic approaches focusing on the abnormal activity-dependent production of toxic TDP43 isoforms.

## Key facts

- **NIH application ID:** 10295762
- **Project number:** 5R01NS113943-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Sami Barmada
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10295762

## Citation

> US National Institutes of Health, RePORTER application 10295762, Atypical TDP43 isoforrms driving neurodegeneration in FTD/ALS (5R01NS113943-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10295762. Licensed CC0.

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