1. Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA
- Author
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Helen C. Miranda, Constanza J. Cortes, Albert R. La Spada, Harald Frankowski, Gwenn A. Garden, Bryce L. Sopher, Jessica E. Young, Nishi Ivanov, Cassiano Carromeu, Yakup Batlevi, Amy Le, and Alysson R. Muotri
- Subjects
Male ,Basic helix-loop-helix leucine zipper transcription factors ,Neurodegenerative ,Transgenic ,Androgen ,Transactivation ,Mice ,Phagosomes ,Receptors ,2.1 Biological and endogenous factors ,Psychology ,Aetiology ,Induced pluripotent stem cell ,Motor Neurons ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,General Neuroscience ,Neurodegeneration ,Cellular Reprogramming ,Muscular Disorders, Atrophic ,Cell biology ,Receptors, Androgen ,Neurological ,Female ,Cognitive Sciences ,medicine.medical_specialty ,Induced Pluripotent Stem Cells ,Mice, Transgenic ,Biology ,Rare Diseases ,Internal medicine ,medicine ,Autophagy ,Animals ,Humans ,Atrophic ,Neurology & Neurosurgery ,Animal ,Neurosciences ,Fibroblasts ,medicine.disease ,Stem Cell Research ,Brain Disorders ,Androgen receptor ,Disease Models, Animal ,Spinal and bulbar muscular atrophy ,Muscular Disorders ,Orphan Drug ,Endocrinology ,Disease Models ,TFEB ,Peptides ,Neuroscience - Abstract
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.
- Published
- 2014