Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration

Naohide Kondo, Masahisa Katsuno (), Hiroaki Adachi, Makoto Minamiyama, Hideki Doi, Shinjiro Matsumoto, Yu Miyazaki, Madoka Iida, Genki Tohnai, Hideaki Nakatsuji, Shinsuke Ishigaki, Yusuke Fujioka, Hirohisa Watanabe, Fumiaki Tanaka, Akira Nakai and Gen Sobue
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Naohide Kondo: Nagoya University Graduate School of Medicine
Masahisa Katsuno: Nagoya University Graduate School of Medicine
Hiroaki Adachi: Nagoya University Graduate School of Medicine
Makoto Minamiyama: Nagoya University Graduate School of Medicine
Hideki Doi: Nagoya University Graduate School of Medicine
Shinjiro Matsumoto: Nagoya University Graduate School of Medicine
Yu Miyazaki: Nagoya University Graduate School of Medicine
Madoka Iida: Nagoya University Graduate School of Medicine
Genki Tohnai: Nagoya University Graduate School of Medicine
Hideaki Nakatsuji: Nagoya University Graduate School of Medicine
Shinsuke Ishigaki: Nagoya University Graduate School of Medicine
Yusuke Fujioka: Nagoya University Graduate School of Medicine
Hirohisa Watanabe: Nagoya University Graduate School of Medicine
Fumiaki Tanaka: Nagoya University Graduate School of Medicine
Akira Nakai: Yamaguchi University School of Medicine
Gen Sobue: Nagoya University Graduate School of Medicine

Nature Communications, 2013, vol. 4, issue 1, 1-14

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms2417

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