Skip Navigation

This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow An erratum has been published
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (80)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Bailey, C. K.
Right arrow Articles by Merry, D. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bailey, C. K.
Right arrow Articles by Merry, D. E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, 2002, Vol. 11, No. 5 515-523
© 2002 Oxford University Press

Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy

Christine K. Bailey1,2, Isabella F. M. Andriola1, Harm H. Kampinga3 and Diane E. Merry1,+

1Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, 208 Bluemle Life Sciences Building, 233 S. 10th Street, Philadelphia, PA 19107, USA, 2Neuroscience Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA, USA and 3Department of Radiation and Stress Cell Biology, University of Groningen, Groningen, The Netherlands

Spinal and bulbar muscular atrophy (SBMA) is one of a growing number of neurodegenerative diseases caused by a polyglutamine-encoding CAG trinucleotide repeat expansion, and is caused by an expansion within exon 1 of the androgen receptor (AR) gene. The family of polyglutamine diseases is characterized by the presence of ubiquitinated, intranuclear inclusions associated with molecular chaperones and 26S proteasome components, although the role of these inclusions in the pathogenesis of polyglutamine diseases remains unclear. The over-expression of molecular chaperones of the Hsp70 and Hsp40 families has been shown to modulate inclusion frequency and cellular toxicity. We developed a cell culture system which enables the quantitative analysis of the effects of molecular chaperones on the biochemical properties of an expanded repeat AR. Using this approach, we demonstrate that Hsp70 and its co-chaperone Hsp40 not only increase expanded repeat AR solubility, but function to enhance the degradation of expanded repeat AR through the proteasome. Furthermore, our studies indicate that these molecular chaperones significantly decrease the half-life of an expanded repeat AR. Molecular chaperone enhancement of protein degradation points to the modulation of molecular chaperones as a potential therapeutic target for polyglutamine diseases.

+ To whom correspondence should be addressed. Tel: +1 215 503 4907; Fax: +1 215 923 9162; Email: diane.merry@mail.tju.edu


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
H. L. Montie, M. S. Cho, L. Holder, Y. Liu, A. S. Tsvetkov, S. Finkbeiner, and D. E. Merry
Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy
Hum. Mol. Genet., June 1, 2009; 18(11): 1937 - 1950.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
K. Tokui, H. Adachi, M. Waza, M. Katsuno, M. Minamiyama, H. Doi, K. Tanaka, J. Hamazaki, S. Murata, F. Tanaka, et al.
17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse
Hum. Mol. Genet., March 1, 2009; 18(5): 898 - 910.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
P. Garyali, P. Siwach, P. K. Singh, R. Puri, S. Mittal, S. Sengupta, R. Parihar, and S. Ganesh
The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system
Hum. Mol. Genet., February 15, 2009; 18(4): 688 - 700.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
Y. Morishima, A. M. Wang, Z. Yu, W. B. Pratt, Y. Osawa, and A. P. Lieberman
CHIP deletion reveals functional redundancy of E3 ligases in promoting degradation of both signaling proteins and expanded glutamine proteins
Hum. Mol. Genet., December 15, 2008; 17(24): 3942 - 3952.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. Mishra, P. Dikshit, S. Purkayastha, J. Sharma, N. Nukina, and N. R. Jana
E6-AP Promotes Misfolded Polyglutamine Proteins for Proteasomal Degradation and Suppresses Polyglutamine Protein Aggregation and Toxicity
J. Biol. Chem., March 21, 2008; 283(12): 7648 - 7656.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J.-i. Niwa, S.-i. Yamada, S. Ishigaki, J. Sone, M. Takahashi, M. Katsuno, F. Tanaka, M. Doyu, and G. Sobue
Disulfide Bond Mediates Aggregation, Toxicity, and Ubiquitylation of Familial Amyotrophic Lateral Sclerosis-linked Mutant SOD1
J. Biol. Chem., September 21, 2007; 282(38): 28087 - 28095.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
H. Adachi, M. Waza, K. Tokui, M. Katsuno, M. Minamiyama, F. Tanaka, M. Doyu, and G. Sobue
CHIP Overexpression Reduces Mutant Androgen Receptor Protein and Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model
J. Neurosci., May 9, 2007; 27(19): 5115 - 5126.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S.-i. Yamada, J.-i. Niwa, S. Ishigaki, M. Takahashi, T. Ito, J. Sone, M. Doyu, and G. Sobue
Archaeal Proteasomes Effectively Degrade Aggregation-prone Proteins and Reduce Cellular Toxicities in Mammalian Cells
J. Biol. Chem., August 18, 2006; 281(33): 23842 - 23851.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. Katsuno, C. Sang, H. Adachi, M. Minamiyama, M. Waza, F. Tanaka, M. Doyu, and G. Sobue
Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease
PNAS, November 15, 2005; 102(46): 16801 - 16806.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J.-H. Lee, J. M. Choi, C. Lee, K. J. Yi, and Y. Cho
Structure of a peptide:N-glycanase-Rad23 complex: Insight into the deglycosylation for denatured glycoproteins
PNAS, June 28, 2005; 102(26): 9144 - 9149.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. Carra, M. Sivilotti, A. T. Chavez Zobel, H. Lambert, and J. Landry
HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells
Hum. Mol. Genet., June 15, 2005; 14(12): 1659 - 1669.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Thomas, Z. Yu, N. Dadgar, S. Varambally, J. Yu, A. M. Chinnaiyan, and A. P. Lieberman
The Unfolded Protein Response Modulates Toxicity of the Expanded Glutamine Androgen Receptor
J. Biol. Chem., June 3, 2005; 280(22): 21264 - 21271.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. Helmlinger, J. Bonnet, J.-L. Mandel, Y. Trottier, and D. Devys
Hsp70 and Hsp40 Chaperones Do Not Modulate Retinal Phenotype in SCA7 Mice
J. Biol. Chem., December 31, 2004; 279(53): 55969 - 55977.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
D. G. Hay, K. Sathasivam, S. Tobaben, B. Stahl, M. Marber, R. Mestril, A. Mahal, D. L. Smith, B. Woodman, and G. P. Bates
Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach
Hum. Mol. Genet., July 1, 2004; 13(13): 1389 - 1405.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Klucken, Y. Shin, E. Masliah, B. T. Hyman, and P. J. McLean
Hsp70 Reduces {alpha}-Synuclein Aggregation and Toxicity
J. Biol. Chem., June 11, 2004; 279(24): 25497 - 25502.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
C. Wojcik and M. Di Napoli
Ubiquitin-Proteasome System and Proteasome Inhibition: New Strategies in Stroke Therapy
Stroke, June 1, 2004; 35(6): 1506 - 1518.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. Abu-Baker, C. Messaed, J. Laganiere, C. Gaspar, B. Brais, and G. A. Rouleau
Involvement of the ubiquitin-proteasome pathway and molecular chaperones in oculopharyngeal muscular dystrophy
Hum. Mol. Genet., October 16, 2003; 12(20): 2609 - 2623.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. Michalik and C. Van Broeckhoven
Pathogenesis of polyglutamine disorders: aggregation revisited
Hum. Mol. Genet., October 15, 2003; 12(90002): R173 - 186.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
D. K. Lee and C. Chang
Expression and Degradation of Androgen Receptor: Mechanism and Clinical Implication
J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4043 - 4054.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
N. Hishikawa, J.-i. Niwa, M. Doyu, T. Ito, S. Ishigaki, Y. Hashizume, and G. Sobue
Dorfin Localizes to the Ubiquitylated Inclusions in Parkinson's Disease, Dementia with Lewy Bodies, Multiple System Atrophy, and Amyotrophic Lateral Sclerosis
Am. J. Pathol., August 1, 2003; 163(2): 609 - 619.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
L. M. Mandrusiak, L. K. Beitel, X. Wang, T. C. Scanlon, E. Chevalier-Larsen, D. E. Merry, and M. A. Trifiro
Transglutaminase potentiates ligand-dependent proteasome dysfunction induced by polyglutamine-expanded androgen receptor
Hum. Mol. Genet., July 1, 2003; 12(13): 1497 - 1506.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. T. Chavez Zobel, A. Loranger, N. Marceau, J. R. Theriault, H. Lambert, and J. Landry
Distinct chaperone mechanisms can delay the formation of aggresomes by the myopathy-causing R120G {alpha}B-crystallin mutant
Hum. Mol. Genet., July 1, 2003; 12(13): 1609 - 1620.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. C. Tsai, P. S. Fishman, N. V. Thakor, and G. A. Oyler
Parkin Facilitates the Elimination of Expanded Polyglutamine Proteins and Leads to Preservation of Proteasome Function
J. Biol. Chem., June 6, 2003; 278(24): 22044 - 22055.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. A. Hauser, Y.-J. Li, S. Takeuchi, R. Walters, M. Noureddine, M. Maready, T. Darden, C. Hulette, E. Martin, E. Hauser, et al.
Genomic convergence: identifying candidate genes for Parkinson's disease by combining serial analysis of gene expression and genetic linkage
Hum. Mol. Genet., March 15, 2003; 12(6): 671 - 677.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
H. Adachi, M. Katsuno, M. Minamiyama, C. Sang, G. Pagoulatos, C. Angelidis, M. Kusakabe, A. Yoshiki, Y. Kobayashi, M. Doyu, et al.
Heat Shock Protein 70 Chaperone Overexpression Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model by Reducing Nuclear-Localized Mutant Androgen Receptor Protein
J. Neurosci., March 15, 2003; 23(6): 2203 - 2211.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. L. Walcott and D. E. Merry
Ligand Promotes Intranuclear Inclusions in a Novel Cell Model of Spinal and Bulbar Muscular Atrophy
J. Biol. Chem., December 20, 2002; 277(52): 50855 - 50859.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
H.Y. E. Chan, J. M. Warrick, I. Andriola, D. Merry, and N. M. Bonini
Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila
Hum. Mol. Genet., November 1, 2002; 11(23): 2895 - 2904.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
L. G.G.C. Verhoef, K. Lindsten, M. G. Masucci, and N. P. Dantuma
Aggregate formation inhibits proteasomal degradation of polyglutamine proteins
Hum. Mol. Genet., October 15, 2002; 11(22): 2689 - 2700.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. P. Lieberman, G. Harmison, A. D. Strand, J. M. Olson, and K. H. Fischbeck
Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor
Hum. Mol. Genet., August 15, 2002; 11(17): 1967 - 1976.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.