title: Chaperone and anti-chaperone: two-faced synuclein as stimulator of synaptic evolution.
abstract: Previous studies have shown that beta-synuclein (beta-syn), the homologue of alpha-syn, inhibited alpha-syn aggregation and stabilized Akt cell survival signaling molecule, suggesting that beta-syn was protective against alpha-syn-related neurodegenerative disorders, such as Parkinson's disease and diffuse Lewy body disease. However, emerging evidence argues that the situation may be not so simple. Two missense mutations of beta-syn were identified in familial and sporadic diffuse Lewy body disease, and wild type beta-syn was induced to form fibril structures in vitro, while, alpha-syn was shown to be protective against neurodegeneration caused by deletion of cysteine-string protein-alpha, the presynaptic cochaperone to Hsc70 in mice. Collectively, alpha- and beta-syn are both, but in varying degrees, featured with two opposite properties, namely normal chaperone and anti-chaperone. By reviewing recent progress in syn biology with a particular focus on beta-syn, this manuscript refers to the intriguing possibility that the dual syn proteins might have acquired a driving force for synaptic evolution. Hypothetically, the anti-chaperone syn may provoke stress-induced diverse responses, whereas, the chaperone syn may provide buffering for them, allowing accumulation of nonlethal phenotypic variations in synapses. Consequently, dual syn proteins may cope with forthcoming stresses in the brain by stimulating adaptive evolution. In this context, failure to regulate this process due to various causes, such as gene mutations and environmental risk factors, may result in imperfect adaptability against stresses, leading to neurodegenerative disorders.
authors.affiliation: Department of Chemistry and Metabolism, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Fujita
authors.forename: Jianshe
authors.initials: J
authors.lastname: Wei
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nakai
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Makoto
authors.initials: M
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D018832:Molecular Chaperones / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*; D051843:Synucleins / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; D051843:Synucleins