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- CLINICA NEUROL, 49: 913－916, 2009
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The 50th Annual Meeting of the Japanese Society of Neurology
Molecular therapy targeting protein misfolding and aggregation for the polyglutamine diseases
Yoshitaka Nagai, M.D., Ph.D.
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry
Abnormal aggregation and deposition of misfolded proteins have been recognized as a common molecular pathogenesis of various neurodegenerative diseases including Alzheimer's, Parkinson's, and the polyglutamine (polyQ) diseases. The polyQ diseases, including Huntington's disease and various spinocerebellar ataxias, are caused by abnormal expansions of the polyQ stretch (>35-40) within disease-causative proteins, which are thought to trigger their misfolding and aggregation, leading to their deposition as inclusion bodies, and eventually resulting in neurodegeneration. We found that the expanded polyQ protein undergoes a conformational transition to a β-sheet dominant structure in the monomeric state, triggering cytotoxicity, and subsequently resulting in formation of insoluble amyloid-like fibrillar aggregates. Targeting misfolding and aggregation of the expanded polyQ protein, we demonstrated that QBP1 (PolyQ-Binding Peptide 1: SNWKWWPGIFD) prevents the toxic β-sheet transition and aggregation of the expanded polyQ protein in vitro and suppresses polyQ-induced neurodegeneration in Drosophila. From high-throughput screening of a chemical compound library (46,000), we have identified approximately 100 polyQ aggregate inhibitors as therapeutic candidates so far. We also found that 17-AAG, an HSF1-activating compound, suppresses polyQ-induced neurodegeneration in Drosophila through induction of endogenous molecular chaperones. We propose that our therapeutic strategy targeting protein misfolding and aggregation can also be applied to other neurodegenerative diseases.
Full Text of this Article in Japanese PDF (398K)
(CLINICA NEUROL, 49: 913－916, 2009)
key words: polyglutamine diseases, misfolding, aggregation, β-sheet, molecular chaperone
(Received: 22-May-09)
