# The AR N/C interaction in SBMA - Mechanistic role and therapeutic potential

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2021 · $466,187

## Abstract

Project Summary:
Many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and the
polyglutamine diseases, result from protein misfolding and accumulation due to a variety of 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 pathway leading to
neuronal dysfunction and death is unknown, the evaluation of transgenic mouse and cell models of
these diseases has yielded mechanistic insights to 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 steps
in SBMA pathogenesis that occur in response to hormone binding and to develop therapeutic
approaches based on that understanding. Our previous studies revealed that a specific
conformational state of the AR that occurs upon hormone binding, the N/C interaction, is required for
its aggregation and toxicity; inhibition of the N/C interaction is protective in both in vitro and in vivo
models. Moreover, we found that Ser-16 phosphorylation is required for this protection. We propose
in this application to further understand the mechanism underlying the role of both the AR N/C
interaction and Ser-16 phosphorylation in disease. In addition, we propose to screen selective AR
modulators (SARMs) that prevent the AR N/C interaction for their effects on SBMA pathogenesis,
both in vitro and in vivo. We anticipate that results from these studies will lead us to a new
understanding of the molecular pathogenesis of SBMA and enhance our development of new
therapies for SBMA.

## Key facts

- **NIH application ID:** 10112974
- **Project number:** 5R01NS108191-04
- **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:** $466,187
- **Award type:** 5
- **Project period:** 2018-05-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112974

## Citation

> US National Institutes of Health, RePORTER application 10112974, The AR N/C interaction in SBMA - Mechanistic role and therapeutic potential (5R01NS108191-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112974. Licensed CC0.

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