Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA.

Journal Article (Journal Article)

Macroautophagy (hereafter autophagy) is a key pathway in neurodegeneration. Despite protective actions, autophagy may contribute to neuron demise when dysregulated. Here we consider X-linked spinal and bulbar muscular atrophy (SBMA), a repeat disorder caused by polyglutamine-expanded androgen receptor (polyQ-AR). We found that polyQ-AR reduced long-term protein turnover and impaired autophagic flux in motor neuron-like cells. Ultrastructural analysis of SBMA mice revealed a block in autophagy pathway progression. We examined the transcriptional regulation of autophagy and observed a functionally significant physical interaction between transcription factor EB (TFEB) and AR. Normal AR promoted, but polyQ-AR interfered with, TFEB transactivation. To evaluate physiological relevance, we reprogrammed patient fibroblasts to induced pluripotent stem cells and then to neuronal precursor cells (NPCs). We compared multiple SBMA NPC lines and documented the metabolic and autophagic flux defects that could be rescued by TFEB. Our results indicate that polyQ-AR diminishes TFEB function to impair autophagy and promote SBMA pathogenesis.

Full Text

Cited Authors

  • Cortes, CJ; Miranda, HC; Frankowski, H; Batlevi, Y; Young, JE; Le, A; Ivanov, N; Sopher, BL; Carromeu, C; Muotri, AR; Garden, GA; La Spada, AR

Published Date

  • September 2014

Published In

Volume / Issue

  • 17 / 9

Start / End Page

  • 1180 - 1189

PubMed ID

  • 25108912

Pubmed Central ID

  • PMC4180729

Electronic International Standard Serial Number (EISSN)

  • 1546-1726

International Standard Serial Number (ISSN)

  • 1097-6256

Digital Object Identifier (DOI)

  • 10.1038/nn.3787


  • eng