# Deciphering TDP-43 Proteinopathy: Unveiling the Consequences on Oligodendrocyte Dysfunction

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2024 · $787,095

## Abstract

TAR-DNA binding protein 43 (TDP-43) is a nuclear protein that has been implicated in several neurodegenerative
diseases, including Frontotemporal Lobar Degeneration (FTLD-TDP), Amyotrophic Lateral Sclerosis (ALS), and
Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC), among other age-related dementias. The
presence of TDP-43 aggregates in the cytoplasm of neurons and glial cells, particularly in oligodendrocytes
(OLs), is the neuropathological hallmark of FTLD-TDP, ALS, and LATE-NC. Similar to other misfolded proteins
(i.e., α-synuclein, β-amyloid and Tau), the transmission of pathogenic TDP-43 species between cells could
contribute to disease progression in neurodegenerative diseases. Our group has recently shown that
pathological TDP-43 derived from FTLD-TDP brain extracts can act as pathogenic seeds and induce the
formation of de novo TDP-43 pathology when injected in the brain of TDP-43 transgenic mice, and to a lesser
extent in wild-type mice (WT). Under this paradigm, TDP-43 pathology spreads throughout the brain in a regional
and time-dependent manner. Interestingly, as found in diseased human brains, TDP-43 pathology is present in
neurons and OLs. Despite several studies indicating that TDP-43 pathology in OLs is a common feature of
various neurodegenerative diseases, including AD and FTLD-TDP, the consequences of TDP-43 pathology in
OLs remains unknown. The present research project aims to develop in vitro models to study the
pathophysiological consequences of TDP-43 pathology in OLs and evaluate the role of OLs in facilitating the
spread of TDP-43 pathogenic species between glial and neuronal cells.

## Key facts

- **NIH application ID:** 10883862
- **Project number:** 1R21AG087070-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Silvia Porta Antolinez
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $787,095
- **Award type:** 1
- **Project period:** 2024-06-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883862

## Citation

> US National Institutes of Health, RePORTER application 10883862, Deciphering TDP-43 Proteinopathy: Unveiling the Consequences on Oligodendrocyte Dysfunction (1R21AG087070-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10883862. Licensed CC0.

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