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Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA
- Source :
- Nature neuroscience, vol 17, iss 9
- Publication Year :
- 2014
- Publisher :
- eScholarship, University of California, 2014.
-
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.
- 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
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Nature neuroscience, vol 17, iss 9
- Accession number :
- edsair.doi.dedup.....71d3954e04d345adab941aa66434b860