Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease.
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.
Katsuno
Masahisa
M
Department of Neurology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan.
Sang
Chen
C
Adachi
Hiroaki
H
Minamiyama
Makoto
M
Waza
Masahiro
M
Tanaka
Fumiaki
F
Doyu
Manabu
M
Sobue
Gen
G
D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D016472:Motor Neuron Disease / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D010455:Peptides / Q000633:toxicity*; D011944:Receptors, Androgen / Q000378:metabolism
D004224:Diterpenes; D006360:Heat-Shock Proteins; D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine; C031049:geranylgeranylacetone