Stimulatory effect of α-synuclein on the tau-phosphorylation by GSK-3ß

Hyperphosphorylation of tau protein (tau) causes neurodegenerative diseases such as Alzheimers disease (AD). Recent studies of the physiological correlation between tau and a-synuclein (a-SN) have demonstrated that: (a) phosphorylated tau is also present in Lewy bodies, which are cytoplasmic inclusions formed by abnormal aggregation of a-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 a-SN in cultured neuronal cells, and also in mice. However, the molecular mechanism responsible for the a-SN-mediated hyperphosphorylation of tau remains to be elucidated. In this in vitro study, we found that: (a) a-SN directly stimulates the phosphorylation of tau by glycogen synthase kinase-3 beta (GSK-3 beta), (b) a-SN forms a heterotrimeric complex with tau and GSK-3 beta, and (c) the nonamyloid beta component (NAC) domain and an acidic region of a-SN are responsible for the stimulation of GSK-3 beta-mediated tau phosphorylation. Thus, it is concluded that a-SN functions as a connecting mediator for tau and GSK-3 beta, resulting in GSK-3 beta-mediated tau phosphorylation. Because the expression of a-SN is promoted by oxidative stress, the accumulation of a-SN induced by such stress may directly induce the hyperphosphorylation of tau by GSK-3 beta. Furthermore, we found that heat shock protein 70 (Hsp70) suppresses the a-SN-induced phosphorylation of tau by GSK-3 beta through its direct binding to a-SN, suggesting that Hsp70 acts as a physiological suppressor of a-SN-mediated tau hyperphosphorylation. These results suggest that the cellular level of Hsp70 may be a novel therapeutic target to counteract a-SN-mediated tau phosphorylation in the initial stage of neurodegenerative disease.