# The role of the AR interactome in SBMA

> **NIH NIH R37** · THOMAS JEFFERSON UNIVERSITY · 2024 · $704,752

## 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 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. The
cell and mouse models of SBMA used within this proposal 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 multiple quantitative proteomics approaches to identify changes in AR protein interaction
networks caused by polyQ expansion in a cell model, and in the previous funding period, we established
an important role for one of these interacting proteins, USP7, in SBMA pathogenesis, validating this
approach to understand disease mechanisms. We propose here to 1) carry out additional interactome
screens in SBMA cell models and in spinal cord and muscle tissues of a validated mouse model of
SBMA and begin the investigation into the roles of these differentially interacting proteins, 2) continue
our mechanistic studies of the role of USP7, and of other differential interactors, in SBMA, and 3)
develop a novel therapeutic approach to specifically target the USP7-AR interaction 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:** 10905560
- **Project number:** 2R37NS108114-06A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** DIANE E MERRY
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $704,752
- **Award type:** 2
- **Project period:** 2018-05-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10905560

## Citation

> US National Institutes of Health, RePORTER application 10905560, The role of the AR interactome in SBMA (2R37NS108114-06A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10905560. Licensed CC0.

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