# The role of TDP-43 in oligodendrocytes

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2020 · $30,760

## Abstract

PROJECT SUMMARY
 TDP-43 is a DNA/RNA binding protein that serves as the global regulator of cellular RNA metabolism.
Although TDP-43 has been extensively studied in neurons with regard to neurodegenerative diseases, its role
in oligodendrocytes has never been addressed. The loss of TDP-43 function, as indicated by nuclear clearance
of TDP-43 and proteinopathy, in oligodendrocytes has been observed in many neurodegenerative diseases as
indicated by nuclear clearance of TDP-43 and proteinopathy. Mature oligodendrocytes in the brain play a
diverse set of functions, including generating myelin sheaths along neuronal axons to allow saltatory
conduction of action potentials, providing metabolic support to neurons and modulating extracellular K+
homeostasis. It remains to be determined if TDP-43 dysfunction in oligodendrocytes disrupts oligodendrocyte
function and further contributes to the pathophysiology of neurodegenerative diseases.
 Preliminary studies using transgenic mice with a genetic deletion of TDP-43 specifically in mature
oligodendrocytes revealed that the loss of TDP-43 confers structural abnormalities in oligodendrocytes that
may be visualized histologically and via in vivo two-photon imaging. These structural changes involved the
presence of aberrant cytoplasmic processes that form loops and tangles and inappropriately associate with
neuronal somata and blood vessels. Given that oligodendrocytes normally show an exquisite selectivity of
myelination in vivo, where only neuronal axons associate with oligodendrocyte processes, it is intriguing how
the loss of TDP-43 induces such dramatic deficits in oligodendrocytes to recognize environmental and cellular
cues to regulate their target-selectivity. Furthermore, the mice with oligodendrocyte-specific TDP-43 deletion
exhibited spontaneous seizures and accelerated death accompanied by deficits in motor behaviors.
 The overarching hypothesis of this proposal is that the loss of TDP-43 in oligodendrocytes disrupts
morphological structures, target-selectivity and function that ultimately culminate in neuronal
hyperexcitability, neurodegeneration and neuroinflammation. I will test this hypothesis by employing a
specific genetic deletion of TDP-43 in oligodendrocytes, conducting in vivo two-photon imaging, performing
extensive histological analyses, and using electrophysiology and video-EEG. In Aim 1, I will determine if the
selective loss of TDP-43 affects the dynamics of oligodendrocytes and oligodendrocyte lineage cells. In Aim 2,
I will further characterize and define the aberrant interaction of abnormal oligodendrocyte processes with
neuronal cell bodies and blood vessels. Lastly, in Aim 3, I will determine if the dysfunction of oligodendrocytes
due to the loss of TDP-43 results in the alteration of neuronal excitability, neurodegeneration and
neuroinflammation. These studies will extend our knowledge about the cell-type specific role of TDP-43 and
how TDP-43 dysfunction in oligodendrocytes con...

## Key facts

- **NIH application ID:** 9989910
- **Project number:** 5F31NS110204-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Dongeun Heo
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $30,760
- **Award type:** 5
- **Project period:** 2018-09-30 → 2021-03-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989910

## Citation

> US National Institutes of Health, RePORTER application 9989910, The role of TDP-43 in oligodendrocytes (5F31NS110204-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989910. Licensed CC0.

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