Journal
BRAIN RESEARCH
Volume 1628, Issue -, Pages 254-264Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.brainres.2015.09.033
Keywords
Polyglutamine; Androgen receptor; Spinal and bulbar muscular atrophy; Protein aggregation
Categories
Funding
- NIH [R01 NS032214, R01 NS076919]
- Thomas Jefferson University
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Polyglutamine-repeat disorders are part of a larger family of neurodegenerative diseases characterized by protein misfolding and aggregation. In spinal and bulbar muscular atrophy (SBMA), polyglutamine expansion within the androgen receptor (AR) causes progressive debilitating muscular atrophy and lower motor neuron loss in males. Although soluble polyglutamine-expanded aggregation species are considered toxic intermediates in the aggregation process, relatively little is known about the spectrum of structures that are formed. Here we identify novel polyglutamine-expanded AR aggregates that are SDS-soluble and bind the toxicity-predicting antibody 3B5H10. Soluble, 3B5H10-reactive aggregation species exist in low-density conformations and are larger by atomic force microscopy, suggesting that they may be less compact than later-stage, insoluble aggregates. We demonstrate disease-relevance in vivo and draw correlations with toxicity in vitro. This article is part of a Special Issue entitled SI: Neuroprotection. (C) 2015 Elsevier B.V. All rights reserved.
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