Document Type
Article
Publication Date
7-16-2024
Abstract
Spinal and bulbar muscular atrophy (SBMA) is a slowly progressing neuromuscular disease caused by a polyglutamine (polyQ)-encoding CAG trinucleotide repeat expansion in the androgen receptor (AR) gene, leading to AR aggregation, lower motor neuron death, and muscle atrophy. AR is a ligand-activated transcription factor that regulates neuronal architecture and promotes axon regeneration; however, whether AR transcriptional functions contribute to disease pathogenesis is not fully understood. Using a differentiated PC12 cell model of SBMA, we identified dysfunction of polyQ-expanded AR in its regulation of neurite growth and maintenance. Specifically, we found that in the presence of androgens, polyQ-expanded AR inhibited neurite outgrowth, induced neurite retraction, and inhibited neurite regrowth. This dysfunction was independent of polyQ-expanded AR transcriptional activity at androgen response elements (ARE). We further showed that the formation of polyQ-expanded AR intranuclear inclusions promoted neurite retraction, which coincided with reduced expression of the neuronal differentiation marker β-III-Tubulin. Finally, we revealed that cell death is not the primary outcome for cells undergoing neurite retraction; rather, these cells become senescent. Our findings reveal that mechanisms independent of AR canonical transcriptional activity underly neurite defects in a cell model of SBMA and identify senescence as a pathway implicated in this pathology. These findings suggest that in the absence of a role for AR canonical transcriptional activity in the SBMA pathologies described here, the development of SBMA therapeutics that preserve this activity may be desirable. This approach may be broadly applicable to other polyglutamine diseases such as Huntington's disease and spinocerebellar ataxias.
Recommended Citation
Karliner, Jordyn; Liu, Y; and Merry, Diane, "Mutant Androgen Receptor Induces Neurite Loss and Senescence Independently of ARE Binding in a Neuronal Model of SBMA" (2024). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 261.
https://jdc.jefferson.edu/bmpfp/261
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
38976730
Language
English
Included in
Biochemistry Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Molecular Biology Commons
Comments
This article is the author's final published version in Proceedings of the National Academy of Sciences of the United States of America, Volume 121, Issue 29, July 2024, Article number e2321408121.
The published version is available at https://doi.org/10.1073/pnas.2321408121.
Copyright © s024 the Author(s). Published by PNAS.