title: Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA.
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.
authors.affiliation: 1] Department of Pediatrics, University of California, San Diego, La Jolla, California, USA. [2].
authors.forename: Constanza J
authors.initials: CJ
authors.lastname: Cortes
authors.affiliation: 1] Department of Pediatrics, University of California, San Diego, La Jolla, California, USA. [2] Department of Cellular &Molecular Medicine, University of California, San Diego, La Jolla, California, USA. [3].
authors.forename: Helen C
authors.initials: HC
authors.lastname: Miranda
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
authors.forename: Harald
authors.initials: H
authors.lastname: Frankowski
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
authors.forename: Yakup
authors.initials: Y
authors.lastname: Batlevi
authors.affiliation: Department of Cellular &Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Young
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Le
authors.affiliation: 1] Center on Human Development &Disability, University of Washington, Seattle, Washington, USA. [2] Department of Neurology, University of Washington, Seattle, Washington, USA.
authors.forename: Nishi
authors.initials: N
authors.lastname: Ivanov
authors.affiliation: Department of Neurology, University of Washington, Seattle, Washington, USA.
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
authors.forename: Cassiano
authors.initials: C
authors.lastname: Carromeu
authors.affiliation: 1] Department of Pediatrics, University of California, San Diego, La Jolla, California, USA. [2] Department of Cellular &Molecular Medicine, University of California, San Diego, La Jolla, California, USA. [3] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [4] Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA. [5] Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California, USA. [6] Rady Children's Hospital, San Diego, California, USA.
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
authors.affiliation: 1] Center on Human Development &Disability, University of Washington, Seattle, Washington, USA. [2] Department of Neurology, University of Washington, Seattle, Washington, USA.
authors.forename: Gwenn A
authors.initials: GA
authors.lastname: Garden
authors.affiliation: 1] Department of Pediatrics, University of California, San Diego, La Jolla, California, USA. [2] Department of Cellular &Molecular Medicine, University of California, San Diego, La Jolla, California, USA. [3] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [4] Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA. [5] Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California, USA. [6] Rady Children's Hospital, San Diego, California, USA. [7] Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D065150:Cellular Reprogramming / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D020966:Muscular Disorders, Atrophic / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000378:metabolism*; D010588:Phagosomes / Q000502:physiology; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D010455:Peptides; D011944:Receptors, Androgen; C064972:TFEB protein, human; C484068:Tcfeb protein, mouse; C097188:polyglutamine
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