Modulation of Hsp90 function in neurodegenerative disorders : a molecular-targeted therapy against disease-causing protein

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2006-08, Vol.84 (8), p.635-646
• Main Authors: WAZA, Masahiro, ADACHI, Hiroaki, KATSUNO, Masahisa, MINAMIYAMA, Makoto, TANAKA, Fumiaki, DOYU, Manabu, SOBUE, Gen
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Benzoquinones - pharmacology; Benzoquinones - therapeutic use; Biological and medical sciences; General aspects; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - physiology; Lactams, Macrocyclic - pharmacology; Lactams, Macrocyclic - therapeutic use; Medical sciences; Mice; Motor Neurons - drug effects; Motor Neurons - pathology; Muscular Disorders, Atrophic - drug therapy; Muscular Disorders, Atrophic - metabolism; Muscular Disorders, Atrophic - pathology; Mutation; Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Peptides - genetics; Proteasome Endopeptidase Complex - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-006-0066-0

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.