Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone

David L. Stenoien; Chris J. Cummings; Henry P. Adams; Maureen G. Mancini; Kavita Patel; George N. Demartino; Marco Marcelli; Nancy L. Weigel; Michael A. Mancini

doi:10.1093/hmg/8.5.731

Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone

David L. Stenoien, Chris J. Cummings, Henry P. Adams, Maureen G. Mancini, Kavita Patel, George N. Demartino, Marco Marcelli, Nancy L. Weigel, Michael A. Mancini

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Abstract

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.

Original language	English (US)
Pages (from-to)	731-741
Number of pages	11
Journal	Human molecular genetics
Volume	8
Issue number	5
DOIs	https://doi.org/10.1093/hmg/8.5.731
State	Published - 1999

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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10.1093/hmg/8.5.731

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Stenoien, D. L., Cummings, C. J., Adams, H. P., Mancini, M. G., Patel, K., Demartino, G. N., Marcelli, M., Weigel, N. L., & Mancini, M. A. (1999). Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone. Human molecular genetics, 8(5), 731-741. https://doi.org/10.1093/hmg/8.5.731

Stenoien, DL, Cummings, CJ, Adams, HP, Mancini, MG, Patel, K, Demartino, GN, Marcelli, M, Weigel, NL & Mancini, MA 1999, 'Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone', Human molecular genetics, vol. 8, no. 5, pp. 731-741. https://doi.org/10.1093/hmg/8.5.731

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title = "Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone",

abstract = "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.",

author = "Stenoien, {David L.} and Cummings, {Chris J.} and Adams, {Henry P.} and Mancini, {Maureen G.} and Kavita Patel and Demartino, {George N.} and Marco Marcelli and Weigel, {Nancy L.} and Mancini, {Michael A.}",

note = "Funding Information: The authors wish to thank Huda Zoghbi, Guido Jenster, Don DeFranco, Angelo Poletti and Walter Ward for many helpful discussions and critical evaluation of experimental data. Ed Yeh is thanked for sharing the NEDD8 antibody. The microscopy in this study was performed in the Integrated Microscopy Core, Center for Reproductive Biology, Department of Cell Biology (NIH HD-07165). These studies were supported in part by a Scientist Development Grant from the National American Heart Association (M.A.M.), a post-doctoral fellowship to D.L.S. (NIH 1F32DK09787-01), NIH grant CA68615 (N.L.W. and M.A.M.), NIH grant DK46181 (G.N.D.) and NIH grant CA68615 (M.M.).",

year = "1999",

doi = "10.1093/hmg/8.5.731",

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AU - Adams, Henry P.

AU - Mancini, Maureen G.

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AU - Demartino, George N.

AU - Marcelli, Marco

AU - Weigel, Nancy L.

AU - Mancini, Michael A.

N1 - Funding Information: The authors wish to thank Huda Zoghbi, Guido Jenster, Don DeFranco, Angelo Poletti and Walter Ward for many helpful discussions and critical evaluation of experimental data. Ed Yeh is thanked for sharing the NEDD8 antibody. The microscopy in this study was performed in the Integrated Microscopy Core, Center for Reproductive Biology, Department of Cell Biology (NIH HD-07165). These studies were supported in part by a Scientist Development Grant from the National American Heart Association (M.A.M.), a post-doctoral fellowship to D.L.S. (NIH 1F32DK09787-01), NIH grant CA68615 (N.L.W. and M.A.M.), NIH grant DK46181 (G.N.D.) and NIH grant CA68615 (M.M.).

PY - 1999

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N2 - 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.

AB - 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.

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Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone

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