Genistein, a natural product derived from soybeans, ameliorates polyglutamine-mediated motor neuron disease.
Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem, and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. AR-associated coregulator 70 (ARA70) was the first coregulator of AR to be identified, and it has been shown to interact with AR and increase its protein stability. Here, we report that genistein, an isoflavone found in soy, disrupts the interaction between AR and ARA70 and promotes the degradation of mutant AR in neuronal cells and transgenic mouse models of SBMA. We also demonstrate that dietary genistein ameliorates behavioral abnormalities, improves spinal cord and muscle pathology, and decreases the amounts of monomeric AR and high-molecular-weight mutant AR protein aggregates in SBMA transgenic mice. Thus, genistein treatment may be a potential therapeutic approach for alleviating the symptoms of SBMA by disrupting the interactions between AR and ARA70.
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Qiang
Q
Qiang
Hiroaki
H
Adachi
Zhe
Z
Huang
Yue-Mei
YM
Jiang
Masahisa
M
Katsuno
Makoto
M
Minamiyama
Hideki
H
Doi
Shinjiro
S
Matsumoto
Naohide
N
Kondo
Yu
Y
Miyazaki
Madoka
M
Iida
Genki
G
Tohnai
Gen
G
Sobue
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D019833:Genistein / Q000494:pharmacology*; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D016472:Motor Neuron Disease / Q000139:chemically induced* / Q000517:prevention & control*; D018482:Muscle, Skeletal / Q000473:pathology; D020966:Muscular Disorders, Atrophic / Q000235:genetics / Q000473:pathology; D018696:Neuroprotective Agents; D056918:Nuclear Receptor Coactivators / Q000235:genetics / Q000502:physiology; D010455:Peptides / Q000502:physiology*; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology
D018076:DNA, Complementary; C508724:NcoA4 protein, mouse; D018696:Neuroprotective Agents; D056918:Nuclear Receptor Coactivators; D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine; D019833:Genistein; D008156:Luciferases; D019950:Mitogen-Activated Protein Kinase 1