Polyglutamine-Expanded Androgen Receptors Form Aggregates That Sequester Heat Shock Proteins, Proteasome Components and SRC-1, and Are Suppressed by the HDJ-2 Chaperone

• Published in: Human molecular genetics 1999-05, Vol.8 (5), p.731-741
• Main Authors: Stenoien, David L., Cummings, Chris J., Adams, Henry P., Mancini, Maureen G., Patel, Kavita, DeMartino, George N., Marcelli, Marco, Weigel, Nancy L., Mancini, Michael A.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Biological and medical sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Nucleus - metabolism; Cysteine Endopeptidases - metabolism; Cytoplasm - metabolism; Cytoplasm - ultrastructure; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Green Fluorescent Proteins; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; HeLa Cells - drug effects; HeLa Cells - metabolism; Histone Acetyltransferases; HSP40 Heat-Shock Proteins; Humans; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Medical sciences; Mitosis; Multienzyme Complexes - metabolism; NEDD8 Protein; Neurology; Nuclear Receptor Coactivator 1; Peptides - genetics; Peptides - metabolism; Proteasome Endopeptidase Complex; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Receptors, Steroid - genetics; Receptors, Steroid - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Transcription Factors - metabolism; Ubiquitins - genetics; Ubiquitins - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/8.5.731

Spinal bulbar muscular atrophy is a neurodegenerative disorder caused by a polyglutamine expansion in the androgen receptor (AR). We show in transiently transfected HeLa cells that an AR containing 48 glutamines (ARQ48) accumulates in a hormone-dependent manner in both cytoplasmic and nuclear aggregates. Electron microscopy reveals both types of aggregates to have a similar ultrastructure. ARQ48 aggregates sequester mitochondria and steroid receptor coactivator 1 and stain positively for NEDD8, Hsp70, Hsp90 and HDJ-2/HSDJ. Co-expression of HDJ-2/HSDJ significantly represses aggregate formation. ARQ48 aggregates also label with antibodies recognizing the PA700 proteasome caps but not 20S core particles. These results suggest that ARQ48 accumulates due to protein misfolding and a breakdown in proteolytic processing. Furthermore, the homeostatic disturbances associated with aggregate formation may affect normal cell function.