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

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder that results from a polyglutamine repeat expansion in the androgen receptor (polyQ-AR). In this study, the authors show that autophagy is dysregulated in SBMA mice and in neural precursors obtained from iPSCs derived from human patients and that this results from an impaired interaction between AR and the transcription factor TFEB. 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.