# Assembling the Genetic Architecture of X-linked Dystonia Parkinsonism

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $663,716

## Abstract

ABSTRACT
X-linked dystonia-parkinsonism (XDP) is a fully penetrant and lethal neurodegenerative disorder in which
symptoms of dystonia overlap with degenerative parkinsonism, reflective of the gradual loss of striatal neurons
as the disease progresses. XDP represents a unique Mendelian disorder that offers the opportunity to study
dysfunction in the basal ganglia given the genetic, mechanistic, and phenotypic overlaps with other forms of
dystonia, Parkinson’s disease, Huntington’s disease, and the tauopathies. Our initially funded program
developed an innovative genome and transcriptome assembly approach, coupled with extensive neuronal
modeling, to discover that an SVA insertion into intron 32 of the TAF1 gene was associated aberrant
transcriptional signatures that included intron retention (IR) and alternative splicing (AS), as well as reduction of
TAF1 expression in patient derived neural stem cells (NSCs) and induced neurons (iNs). This mutation was also
associated with global changes in neurodevelopmental and inflammation pathways, consistent with the functions
of TAF1 as a key transcriptional regulator. We surprisingly found that age-at-onset and disease expression were
modified by a variable hexameric repeat within the SVA, and that CRISPR-excision of the SVA rescued all
transcriptional aberrations in XDP, suggesting a path to amelioration. In this renewal, we will leverage strong
new preliminary results that suggest: 1) antisense oligonucleotides (ASO) can alter TAF1 splicing in XDP; 2) all
molecular signatures discovered in neuronal cell models are confirmed in postmortem brain tissue from XDP
cases and are tissue-specific; 3) there is clear evidence of tau accumulation in XDP postmortem brain tissues.
To pursue our foundational discoveries and new findings, we will conduct a series of studies across a highly
complementary team of investigators to define the pathogenic mechanisms and possible targeted therapies for
XDP. Aim 1 will apply ASO therapies to manipulate AS and IR in neuronal models and modulate TAF1
expression, then explore the perturbation and rescue of molecular signatures. Aim 2 will use a unique XDP brain
bank to study the transcriptomic and proteopathic features of XDP in postmortem brains, where our preliminary
data indicate that neuropathologic changes in XDP are consistent with a previously unrecognized tauopathy. We
will systematically profile and quantify the burden of tau across multiple brain regions, as well as the biochemical
and structural characteristics of pathologic tau in XDP. Using patient biosamples, we will also seek potential
biomarkers of this pathology. Aim 3 will then integrate ASO/CRISPR targeting and tau dynamics with prior data
that support a role for inflammation and iron-mediated toxicity in XDP. We will develop neuron:glial co-cultures,
and characterize the responses of these cell types to tau, iron, and inflammatory stimuli. These interdisciplinary
and interconnected aims will provide broad mec...

## Key facts

- **NIH application ID:** 10825890
- **Project number:** 2R01NS102423-06
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** David Cristopher Bragg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $663,716
- **Award type:** 2
- **Project period:** 2017-09-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825890

## Citation

> US National Institutes of Health, RePORTER application 10825890, Assembling the Genetic Architecture of X-linked Dystonia Parkinsonism (2R01NS102423-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10825890. Licensed CC0.

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