# Role of DYT6 Dystonia Protein THAP1 in Oligodendroglial Mediated ECM Homeostasis During CNS Development

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $413,450

## Abstract

Abstract / Project Summary
The brain extracellular matrix (ECM) is a complex three-dimensional milieu that has a profound
influence on synaptic plasticity and myelination during development. The pathways and cell types
driving ECM generation during brain development are poorly understood. This proposal investigates a
recently identified cellular pathway that controls ECM composition from the oligodendrocyte progenitor
cells (OPCs). This discovery was made through studies of the transcription factor THAP1, which is
mutated in the neurodevelopmental movement disorder DYT-THAP1 (DYT6) dystonia. Previous work
identified a critical role for THAP1 in developmental myelination. Loss of THAP1 in the oligodendrocyte
(OL) lineage impairs the progression of OPC into mature myelinating OLs. Recent work has established
that THAP1 mediates OL differentiation in large part by controlling the composition of secreted
chondroitin sulfate (CS) GAGs, a class of long unbranched polysaccharides and core-constituents of
the ECM, which are inhibitory to OL differentiation. The hypothesis that OPCs regulate ECM
composition is new, and the transcription factor THAP1, together with its partner YY1, provides an
inroad to delineating the cellular mechanisms that regulate ECM composition during CNS development.
The proposed studies will establish a molecular understanding of the regulation of ECM and myelination
by THAP1. Aim 1 will use ChIP-seq and transcriptomic studies to test the hypothesis that THAP1 and
its co-regulatory transcription factor YY1 regulate GAG metabolism through a shared pathway in
differentiating OPCs. Both transcription factors have established roles in myelination and cause human
dystonia when mutated. Aim 2 will test the hypothesis that OPCs are important contributors to
developmentally regulated CS-GAG composition of the brain ECM and define the relative contribution
of other CNS cell types, and the role of THAP1 in this process. Aim 3 test the hypothesis that THAP1-
dependent OL maturation is required for normal motor learning and define THAP1-dependent changes
in ECM pathway genes induced by motor learning. These studies will advance our understanding of
the mechanisms by which glia and ECM contribute to CNS motor function and will shed light on how
disruption of these processes contribute to pathogenesis of dystonia and other neurodevelopmental
disorders.

## Key facts

- **NIH application ID:** 10863834
- **Project number:** 5R01NS122990-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** WILLIAM T. DAUER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $413,450
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863834

## Citation

> US National Institutes of Health, RePORTER application 10863834, Role of DYT6 Dystonia Protein THAP1 in Oligodendroglial Mediated ECM Homeostasis During CNS Development (5R01NS122990-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10863834. Licensed CC0.

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