Linked Life Data

17494697

Source:http://linkedlifedata.com/resource/pubmed/id/17494697

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
19
pubmed:dateCreated
2007-5-14
pubmed:abstractText
Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor (AR). The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of the mutant AR in the residual motor neurons and certain visceral organs. Many components of the ubiquitin-proteasome and molecular chaperones are also sequestered in the inclusions, suggesting that they may be actively engaged in an attempt to degrade or refold the mutant AR. C terminus of Hsc70 (heat shock cognate protein 70)-interacting protein (CHIP), a U-box type E3 ubiquitin ligase, has been shown to interact with heat shock protein 90 (Hsp90) or Hsp70 and ubiquitylates unfolded proteins trapped by molecular chaperones and degrades them. Here, we demonstrate that transient overexpression of CHIP in a neuronal cell model reduces the monomeric mutant AR more effectively than it does the wild type, suggesting that the mutant AR is more sensitive to CHIP than is the wild type. High expression of CHIP in an SBMA transgenic mouse model also ameliorated motor symptoms and inhibited neuronal nuclear accumulation of the mutant AR. When CHIP was overexpressed in transgenic SBMA mice, mutant AR was also preferentially degraded over wild-type AR. These findings suggest that CHIP overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR via enhanced mutant AR degradation. Thus, CHIP overexpression would provide a potential therapeutic avenue for SBMA.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1529-2401
pubmed:author
pubmed:issnType
Electronic
pubmed:day
9
pubmed:volume
27
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5115-26
pubmed:meshHeading
pubmed-meshheading:17494697-Animals, pubmed-meshheading:17494697-Central Nervous System, pubmed-meshheading:17494697-Disease Models, Animal, pubmed-meshheading:17494697-Down-Regulation, pubmed-meshheading:17494697-Female, pubmed-meshheading:17494697-Gene Expression Regulation, pubmed-meshheading:17494697-Gene Therapy, pubmed-meshheading:17494697-Genetic Predisposition to Disease, pubmed-meshheading:17494697-Heat-Shock Proteins, pubmed-meshheading:17494697-Humans, pubmed-meshheading:17494697-Inclusion Bodies, pubmed-meshheading:17494697-Intranuclear Inclusion Bodies, pubmed-meshheading:17494697-Male, pubmed-meshheading:17494697-Mice, pubmed-meshheading:17494697-Mice, Transgenic, pubmed-meshheading:17494697-Motor Neurons, pubmed-meshheading:17494697-Muscular Atrophy, Spinal, pubmed-meshheading:17494697-Mutation, pubmed-meshheading:17494697-Nerve Degeneration, pubmed-meshheading:17494697-Phenotype, pubmed-meshheading:17494697-Proteasome Endopeptidase Complex, pubmed-meshheading:17494697-Protein Folding, pubmed-meshheading:17494697-Receptors, Androgen, pubmed-meshheading:17494697-Ubiquitin-Protein Ligases
pubmed:year
2007
pubmed:articleTitle
CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model.
pubmed:affiliation
Department of Neurology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't