# The mechanism and role of androgen receptor Serine 16 phosphorylation in SBMA

> **NIH NIH R21** · THOMAS JEFFERSON UNIVERSITY · 2024 · $429,000

## Abstract

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. Many 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. Such studies previously revealed that a specific conformational state, the
interaction between the amino (N)- and carboxyl (C)- terminal ends of the AR that occurs upon hormone
binding (N/C interaction), is required for its aggregation and toxicity; inhibition of the N/C interaction by
genetic or pharmacologic means is protective both in vitro and in vivo. Moreover, we found that not only
is Ser-16 hyperphosphorylated upon preventing the AR N/C interaction but this phosphorylation is
required for protection, as mutation of Ser-16 to the un-phosphorylatable amino acid Alanine abrogated
the neuroprotection. We propose in this application to further understand the mechanism underlying the
role of Ser-16 phosphorylation in disease by identifying the kinase responsible for Ser-16
phosphorylation (Aim 1) and using this information to explore the impact of Ser-16 phosphorylation on
AR metabolism and SBMA-related cellular and biochemical phenotypes (Aim 2). 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:** 10952790
- **Project number:** 1R21NS139090-01
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** DIANE E MERRY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $429,000
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10952790

## Citation

> US National Institutes of Health, RePORTER application 10952790, The mechanism and role of androgen receptor Serine 16 phosphorylation in SBMA (1R21NS139090-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10952790. Licensed CC0.

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