Blocking the Dimerization of Polyglutamine-Expanded Androgen Receptor Protects Cells from DHT-Induced Toxicity by Increasing AR Turnover

Authors

Allison Lisberg, Thomas Jefferson University
Yuhong Liu, Thomas Jefferson UniversityFollow
Diane E. Merry, Department of Biochemistry and Molecular Biology, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

3-29-2024

Comments

This article is the author's final published version in Journal of Biological Chemistry, Volume 300, Issue 5, March 2024, Article number 107246.

The published version is available at https://doi.org/10.1016/j.jbc.2024.107246.

Copyright © 2024 THE AUTHOR

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular degenerative disease caused by a polyglutamine expansion in the androgen receptor (AR). This mutation causes AR to misfold and aggregate, contributing to toxicity in and degeneration of motor neurons and skeletal muscle. There is currently no effective treatment or cure for this disease. The role of an interdomain interaction between the amino- and carboxyl-termini of AR, termed the N/C interaction, has been previously identified as a component of androgen receptor-induced toxicity in cell and mouse models of SBMA. However, the mechanism by which this interaction contributes to disease pathology is unclear. This work seeks to investigate this mechanism by interrogating the role of AR homodimerization- a unique form of the N/C-interaction- in SBMA. We show that, although the AR N/C-interaction is reduced by polyglutamine-expansion, homodimers of 5α-dihydrotestosterone (DHT)-bound AR are increased. Additionally, blocking homodimerization results in decreased AR aggregation and toxicity in cell models. Blocking homodimerization results in the increased degradation of AR, which likely plays a role in the protective effects of this mutation. Overall, this work identifies a novel mechanism in SBMA pathology that may represent a novel target for the development of therapeutics for this disease.

Recommended Citation

Lisberg, Allison; Liu, Yuhong; and Merry, Diane E., "Blocking the Dimerization of Polyglutamine-Expanded Androgen Receptor Protects Cells from DHT-Induced Toxicity by Increasing AR Turnover" (2024). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 257.
https://jdc.jefferson.edu/bmpfp/257

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

38556081

Language

English