title: Stimulatory effect of α-synuclein on the tau-phosphorylation by GSK-3β.
abstract: Hyperphosphorylation of tau protein (tau) causes neurodegenerative diseases such as Alzheimer's disease (AD). Recent studies of the physiological correlation between tau and α-synuclein (α-SN) have demonstrated that: (a) phosphorylated tau is also present in Lewy bodies, which are cytoplasmic inclusions formed by abnormal aggregation of α-SN; and (b) the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) increases the phosphorylation of tau as well as the protein level of α-SN in cultured neuronal cells, and also in mice. However, the molecular mechanism responsible for the α-SN-mediated hyperphosphorylation of tau remains to be elucidated. In this in vitro study, we found that: (a) α-SN directly stimulates the phosphorylation of tau by glycogen synthase kinase-3β (GSK-3β), (b) α-SN forms a heterotrimeric complex with tau and GSK-3β, and (c) the nonamyloid beta component (NAC) domain and an acidic region of α-SN are responsible for the stimulation of GSK-3β-mediated tau phosphorylation. Thus, it is concluded that α-SN functions as a connecting mediator for tau and GSK-3β, resulting in GSK-3β-mediated tau phosphorylation. Because the expression of α-SN is promoted by oxidative stress, the accumulation of α-SN induced by such stress may directly induce the hyperphosphorylation of tau by GSK-3β. Furthermore, we found that heat shock protein 70 (Hsp70) suppresses the α-SN-induced phosphorylation of tau by GSK-3β through its direct binding to α-SN, suggesting that Hsp70 acts as a physiological suppressor of α-SN-mediated tau hyperphosphorylation. These results suggest that the cellular level of Hsp70 may be a novel therapeutic target to counteract α-SN-mediated tau phosphorylation in the initial stage of neurodegenerative disease.
authors: Department of Biochemistry, Kitasato University, Minami-ku, Sagamihara, Japan.
authors: Fumitaka
authors: F
authors: Kawakami
authors: Minori
authors: M
authors: Suzuki
authors: Naoki
authors: N
authors: Shimada
authors: Go
authors: G
authors: Kagiya
authors: Etsuro
authors: E
authors: Ohta
authors: Kei
authors: K
authors: Tamura
authors: Hiroko
authors: H
authors: Maruyama
authors: Takafumi
authors: T
authors: Ichikawa
mesh_terms: D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D010766:Phosphorylation; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051846:beta-Synuclein / Q000494:pharmacology; D051845:gamma-Synuclein / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3