Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein.
Abnormal accumulation of disease-causing protein is a commonly observed characteristic in chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and polyglutamine (polyQ) diseases. A therapeutic approach that could selectively eliminate would be a promising remedy for neurodegenerative disorders. Spinal and bulbar muscular atrophy (SBMA), one of the polyQ diseases, is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. The pathogenic gene product is polyQ-expanded androgen receptor (AR), which belongs to the heat shock protein (Hsp) 90 client protein family. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a novel Hsp90 inhibitor, is a new derivative of geldanamycin that shares its important biological activities but shows less toxicity. 17-AAG is now in phase II clinical trials as a potential anti-cancer agent because of its ability to selectively degrade several oncoproteins. We have recently demonstrated the efficacy and safety of 17-AAG in a mouse model of SBMA. The administration of 17-AAG significantly ameliorated polyQ-mediated motor neuron degeneration by reducing the total amount of mutant AR. 17-AAG accomplished the preferential reduction of mutant AR mainly through Hsp90 chaperone complex formation and subsequent proteasome-dependent degradation. 17-AAG induced Hsp70 and Hsp40 in vivo as previously reported; however, its ability to induce HSPs was limited, suggesting that the HSP induction might support the degradation of mutant protein. The ability of 17-AAG to preferentially degrade mutant protein would be directly applicable to SBMA and other neurodegenerative diseases in which the disease-causing proteins also belong to the Hsp90 client protein family. Our proposed therapeutic approach, modulation of Hsp90 function by 17-AAG treatment, has emerged as a candidate for molecular-targeted therapies for neurodegenerative diseases. This review will consider our research findings and discuss the possibility of a clinical application of 17-AAG to SBMA and other neurodegenerative diseases.
Waza
Masahiro
M
Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, 466-8550 Nagoya, Japan.
Adachi
Hiroaki
H
Katsuno
Masahisa
M
Minamiyama
Makoto
M
Tanaka
Fumiaki
F
Doyu
Manabu
M
Sobue
Gen
G
D000367:Age Factors; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D020966:Muscular Disorders, Atrophic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine; C112765:tanespimycin; D046988:Proteasome Endopeptidase Complex