Mutant androgen receptor induces neurite loss and senescence independently of ARE binding in a neuronal model of SBMA

• 成果类型: Article
• 署名作者: Karliner, Jordyn; Liu, Yuhong; Merry, Diane E.
• 署名单位: Thomas Jefferson University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9305
• DOI: 10.1073/pnas.2321408121
• 发表日期: 2024-07-16
• 关键词: bulbar muscular-atrophy; recessive bulbospinal neuronopathy; transgenic mouse model; regenerative properties; nuclear inclusions; motor-neurons; testosterone; expression; protein; disease

摘要

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 beta- 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.