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 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-3b (GSK-3b), (b) a-SN forms a heterotrimeric complex with tau and GSK-3b, and (c) the nonamyloid beta component (NAC) domain and an acidic region of a-SN are responsible for the stimulation of GSK-3b-mediated tau phosphorylation. Thus, it is concluded that a-SN functions as a connecting mediator for tau and GSK-3b, resulting in GSK-3b-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-3b. Furthermore, we found that heat shock protein 70 (Hsp70) suppresses the a-SN-induced phosphorylation of tau by GSK-3b 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. Structured digital abstractl GSK3B phosphorylates GSK3B by protein kinase assay (View interaction) l TAU binds to a-SN by pull down (View interaction) l GSK3B phosphorylates TAU by protein kinase assay (View Interaction: 1, 2, 3, 4) l TAU physically interacts with a-SN and HSP70 by pull down (View interaction) l TAU physically interacts with a-SN and GSK3B by pull down (View interaction) l GSK3B binds to a-SN by pull down (View interaction) Abbreviations GSK-3b, glycogen synthase kinase-3b; GST, glutathione S-transferase; Hsp70, heat shock protein 70; NAC, nonamyloid beta component; a-SN, alpha-synuclein; tau, microtubule-associated protein tau.

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

“…25,26 The aforementioned studies combined with our current results suggest that hyperactivation of GSK-3β may be the primary mechanism by which this protein is linked to PD (Figure 7). Indeed, a growing body of evidence from our laboratory and others define the important roles, kinases, such as GSK-3β, CK2, PLK2 and 3, and GRK1-5 have in the development and pathology of PD through the phosphorylation of α-Syn and Tau 16,[18][19][20][21][22][23][24][53][54][55][56][57] (Supplementary Table S3 and associated references).…”

“…A recent study also showed that in in vitro kinase reactions, GSK3-β-mediated phosphorylation of Tau was increased in the presence of α-Syn in a dose-dependent manner. 57 These cumulative findings demonstrate that both α-Syn and Tau can modulate the toxic production of their phospho-proteins, in a manner that is subtly nuanced (Figure 7). Future experiments will delineate the exact signaling pathways altered by GSK-3β in the hGSK3-β-S9A mouse model, and as such, may provide a more thorough view as to whether phosphorylation of α-Syn occurs directly or indirectly via p-GSK3-β-Y216 and why the occurrence of accumulated p-α-Syn and p-Tau are restricted to the SN.…”

The role of α-synuclein in neurodegeneration — An update

“…Recent postmortem studies showed increased accumulation of p-tau in the striata of PD patients and in the A53T mutant mouse model [343,577], related to increased activity of GSK-3β [566,579]. This is stimulated by AS that associates with the actin cytoskeleton [585] and by GSK-3β [568]. DA D1 receptor activation induces tau phosphorylation via cyclin-dependent kinase 5 (cdk5) and GSK-3β signalling pathways [586].…”

Neuropathology of Parkinson’s Disease

“…Accumulated α-syn (promoted by oxidative stress) has a stimulatory effect on tau phosphorylation by glycogen synthase kinase-3β (GSK-3β), a major kinase that hyperphosphorylates tau to produce pathologic forms [ 242 ], while the chaperone HSP70 may suppress α-syn-mediated tau phosphorylation in initial disease stages [ 243 ]. In MPTP models, α-syn has been shown to induce GSK-3β-catalyzed tau phosphorylation [ 244 , 245 ].…”