NDLI: Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease

Content Provider	PubMed Central
Author	Katsuno, Masahisa Sang, Chen Adachi, Hiroaki Makoto, Minamiyama Masahiro, Waza Tanaka, Fumiaki Doyu, Manabu Sobue, Gen
Copyright Year	2005
Abstract	Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by the expansion of a trinucleotide CAG repeat encoding the polyglutamine tract in the first exon of the androgen receptor gene (AR). The pathogenic, polyglutamine-expanded AR protein accumulates in the cell nucleus in a ligand-dependent manner and inhibits transcription by interfering with transcriptional factors and coactivators. Heat-shock proteins (HSPs) are stress-induced chaperones that facilitate the refolding and, thus, the degradation of abnormal proteins. Geranylgeranylacetone (GGA), a nontoxic antiulcer drug, has been shown to potently induce HSP expression in various tissues, including the central nervous system. In a cell model of SBMA, GGA increased the levels of Hsp70, Hsp90, and Hsp105 and inhibited cell death and the accumulation of pathogenic AR. Oral administration of GGA also up-regulated the expression of HSPs in the central nervous system of SBMA-transgenic mice and suppressed nuclear accumulation of the pathogenic AR protein, resulting in amelioration of polyglutamine-dependent neuromuscular phenotypes. These observations suggest that, although a high dose appears to be needed for clinical effects, oral GGA administration is a safe and promising therapeutic candidate for polyglutamine-mediated neurodegenerative diseases, including SBMA.
Related Links	http://dx.doi.org/10.1073/pnas.0506249102
Ending Page	16806
Page Count	6
Starting Page	16801
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	46
Volume Number	102
Language	English
Publisher	National Academy of Sciences
Publisher Date	2005-11-15
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease.

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Transcriptional induction of the heat shock protein B8 mediates the clearance of misfolded proteins responsible for motor neuron diseases

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Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease

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