# Determinants of cell type-specific vulnerability in Huntington's disease

> **NIH NIH R01** · BROAD INSTITUTE, INC. · 2021 · $35,313

## Abstract

Challenge and Impact: Huntington's disease (HD) is a fatal inherited neurodegenerative disease, and all
cases are caused by CAG trinucleotide repeat expansions in the huntingtin gene. There are currently no
curative therapeutics for HD, and thus there is a critical need for the development of new therapeutic targets.
Striatal medium spiny neurons (MSNs) are thought to be the most affected neuronal cell type in HD, but it is
still not fully understood how huntingtin mutation leads to neuronal cell death in general or MSNs in particular.
Mutant Huntingtin protein (mHTT) is expressed fairly ubiquitously, suggesting that MSNs possess vulnerability
factors or else lack protective factors. If these factors were known, they would advance mechanistic
understanding and point to new HD therapeutic targets. One prominent hypothesis is that huntingtin mutation
leads to a toxic gain-of-function dysregulation of gene expression. Many studies have used gene expression
profiling to study transcriptional dysregulation and its mechanistic basis in HD, but to date these studies have
been limited by anatomical cellular intermixing and thus have not detected genome-wide MSN cell type-
specific changes to gene expression due to signal averaging across cell types. However, such data are
necessary to fully understand whether transcriptional dysregulation is causative or a consequence of mutant
Huntingtin (mHTT) toxicity, and whether MSNs possess distinct vulnerability factors or lack protective factors
either intrinsically or in response to mHTT. The studies outlined in this proposal will advance mechanistic
understanding and point to new therapeutic targets for HD.
Approach: To perform cell type-specific gene expression studies, we have begun to apply the translating
ribosome affinity purification (TRAP) methodology to the study of mouse models of HD. TRAP reports on the
cell type-specific translatome, by allowing cell type-specific translated mRNA immunoprecipitation. Our
preliminary HD model TRAP studies have identified a large number of previously uncharacterized changes to
mRNA translation at an early, pre-symptomatic HD mouse model timepoint, and point to early dysregulation of
forkhead box O1, Foxo1, transcription factor activity in MSNs in response to mHTT. In Aim1, we will perform
cell type-specific TRAP analyses to investigate pre- and post-symptomatic gene expression changes in mouse
models of HD to examine whether MSNs possess distinct HD vulnerability factors or lack HD protective factors
either intrinsically or in response to mHTT. In Aim 2 we will determine the cell type-specific phosphorylation
status, subcellular localization, and transcriptional targets of Foxo1 in MSNs, and how these are altered in HD
model mice. In Aim 3 we will test the phenotypic effects of Foxo1 loss and overexpression in wildtype mice
and HD model mice. If successful, the results of this aim will demonstrate a role for Foxo1 in causing
enhanced vulnerability to mHTT, and thus pro...

## Key facts

- **NIH application ID:** 10137324
- **Project number:** 5R01NS100802-05
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Myriam Heiman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $35,313
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137324

## Citation

> US National Institutes of Health, RePORTER application 10137324, Determinants of cell type-specific vulnerability in Huntington's disease (5R01NS100802-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10137324. Licensed CC0.

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