Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration.
A crucial feature of adult-onset neurodegenerative diseases is accumulation of abnormal protein in specific brain regions, although the mechanism underlying this pathological selectivity remains unclear. Heat shock factor-1 is a transcriptional regulator of heat shock proteins, molecular chaperones that abrogate neurodegeneration by refolding and solubilizing pathogenic proteins. Here we show that heat shock factor-1 expression levels are associated with the accumulation of pathogenic androgen receptor in spinal and bulbar muscular atrophy, a polyglutamine-induced neurodegenerative disease. In heterozygous heat shock factor-1-knockout spinal and bulbar muscular atrophy mice, abnormal androgen receptor accumulates in the cerebral visual cortex, liver and pituitary, which are not affected in their genetically unmodified counterparts. The depletion of heat shock factor-1 also expands the distribution of pathogenic androgen receptor accumulation in other neuronal regions. Furthermore, lentiviral-mediated delivery of heat shock factor-1 into the brain of spinal and bulbar muscular atrophy mice topically suppresses the pathogenic androgen receptor accumulation and neuronal atrophy. These results suggest that heat shock factor-1 influences the pathological lesion selectivity in spinal and bulbar muscular atrophy.
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Naohide
N
Kondo
Masahisa
M
Katsuno
Hiroaki
H
Adachi
Makoto
M
Minamiyama
Hideki
H
Doi
Shinjiro
S
Matsumoto
Yu
Y
Miyazaki
Madoka
M
Iida
Genki
G
Tohnai
Hideaki
H
Nakatsuji
Shinsuke
S
Ishigaki
Yusuke
Y
Fujioka
Hirohisa
H
Watanabe
Fumiaki
F
Tanaka
Akira
A
Nakai
Gen
G
Sobue
D000368:Aged; D000818:Animals; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009044:Motor Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020966:Muscular Disorders, Atrophic / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects; D010455:Peptides / Q000633:toxicity*; D010902:Pituitary Gland / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D019076:Transgenes
D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C490017:Hsf1 protein, mouse; D050505:Mutant Proteins; D010455:Peptides; D011944:Receptors, Androgen; D014157:Transcription Factors; C097188:polyglutamine