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Stimulatory effect of α ‐synuclein on the tau‐phosphorylation by GSK‐3 β
Author(s) -
Kawakami Fumitaka,
Suzuki Minori,
Shimada Naoki,
Kagiya Go,
Ohta Etsuro,
Tamura Kei,
Maruyama Hiroko,
Ichikawa Takafumi
Publication year - 2011
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2011.08389.x
Subject(s) - hyperphosphorylation , phosphorylation , gsk 3 , chemistry , tau protein , gsk3b , microbiology and biotechnology , biology , biochemistry , alzheimer's disease , medicine , disease
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. Structured digital abstract• GSK3B phosphorylates GSK3B by protein kinase assay ( View interaction ) • TAU binds to ‐SN by pull down ( View interaction ) • GSK3B phosphorylates TAU by protein kinase assay (View Interaction: 1 , 2 , 3 , 4 ) • TAU physically interacts with ‐SN and HSP70 by pull down ( View interaction ) • TAU physically interacts with ‐SN and GSK3B by pull down ( View interaction ) • GSK3B binds to ‐SN by pull down ( View interaction ) • GSK3B physically interacts with ‐SN and HSP70 by pull down ( View interaction ) • HSP70 binds to ‐SN by pull down ( View interaction ) • GSK3B phosphorylates Gs by protein kinase assay ( View interaction )