# The Role of the AR Interactome in SBMA

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2021 · $429,270

## Abstract

Project Summary:
Several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, as well as
the polyglutamine expansion diseases, result from protein misfolding and accumulation due to genetic
and/or environmental causes. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, inherited
neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR);
it is related to other neurodegenerative diseases caused by polyglutamine expansion, including
Huntington's disease and several spinocerebellar ataxias. Although the precise pathways leading to
neuronal dysfunction and death are unknown, the evaluation of transgenic mouse and cell models of
these diseases has yielded mechanistic insights into disease pathogenesis. SBMA stands apart from
other polyglutamine diseases in that its onset and progression are dependent on AR androgenic
ligands. Our cell and mouse models of SBMA reproduce the androgen- and polyglutamine-dependent
nuclear AR aggregation seen in patients, as well as its consequent toxicity, making these models
highly useful for the analysis of the mechanistic basis for upstream events involved in AR toxicity. Our
long-term objectives are to use these models to develop a mechanistic understanding of
hormone-dependent, polyglutamine-expanded AR toxicity. A growing body of evidence suggests
that long polyQ tracts cause cellular dysfunction and ultimately cell death, at least in part by
dysregulating protein-protein interactions that sustain normal cellular function. We have utilized a
quantitative proteomics approach to identify changes in the AR protein interaction network caused by
polyQ expansion in a cell model, and identified several protein candidates that may be involved in
polyQ-expanded AR pathogenicity. Our preliminary studies on one of the identified interactors, USP7
(a preferential interactor with polyQ-expanded AR), reveals a role for USP7 in SBMA. We propose
here to 1) carry out additional interactome screens in spinal cord and muscle tissues of a validated
mouse model of SBMA, 2) investigate the roles of the other differentially interacting proteins identified
in our initial screen, and 3) continue our mechanistic studies of the role of USP7 in SBMA. We
anticipate that results from these studies will lead us to a deeper understanding of the molecular
pathogenesis of SBMA, and will yield novel pathways amenable to therapeutic modulation for SBMA.

## Key facts

- **NIH application ID:** 10112972
- **Project number:** 5R01NS108114-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** DIANE E MERRY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $429,270
- **Award type:** 5
- **Project period:** 2018-05-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112972

## Citation

> US National Institutes of Health, RePORTER application 10112972, The Role of the AR Interactome in SBMA (5R01NS108114-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10112972. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*