<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease. The α-Synuclein is a major component of Lewy bodies and Lewy neurites, the pathologic hallmark of PD. It is known that α-Synuclein is phosphorylated (p-α-Synuclein) in PD and tau-hyperphosphorylation (p-Tau) is also a pathologic feature of PD. However, the relationship between p-Synuclein and p-Tau in PD is not clear, in particular in the MPTP model of PD. The purpose of this study was to reveal their relationship in the mouse MPTP model. Methods: Firstly, the p-α-Synuclein, α-Synuclein, p-Tau and Tau protein levels were analyzed. Then, GSK3β activation was determined using immunoblot and immunohistochemical staining. Finally, the dopaminergic neurodegeneration was assessed using Tyrosine Hydroxylase (TH) staining and retrograde labeling and microglial marker were labeled. Microglial activation and nigrostriatal pathway degeneration were observed. Results: The results showed that p-α-Synuclein, α-Synuclein, p-Tau and Tau were upregulated in both hippocampus and substantia nigra of the PD mouse model. Furthermore, p-α-Synuclein and p-Tau were localized in the same regions of substantial nigra (SN) and dentate gyrus (DG) of hippocampus (Hippo). The activated form of GSK3β (phosphor GSK3β Y216) was increased in multiple brain areas. The GSK3β inhibitor AZD1080 injected in MPTP mice suppressed the expression of p-Tau and p-GSK3β and improved motor functions. Conclusion: These findings revealed that p-α-Synuclein and p-Tau proteins are key pathological events leading to neurodegeneration and motor dysfunctions in the mouse MPTP model of PD. Our data suggest that the interference with the GSK3β activity may be an effective approach for the treatment of PD.

Chemokine CXCL13 acts via CXCR5-ERK signaling in hippocampus to induce perioperative neurocognitive disorders in surgically treated mice

“…Brain tissue was immunostained as described [ 24 ]. It was isolated, fixed in 4% paraformaldehyde, placed into paraffin blocks, and cut coronally into 6-μm sections.…”

Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease

“…Furthermore, phosphorylated forms of ASN and Tau have demonstrated co-occurrence in the same brain structure, including in the SN and the hippocampus in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model. Furthermore, glycogen synthase kinase 3 beta (GSK-3β) inhibition reduced numbers of p-Tau positive cells, which was accompanied by improved motor performance [70]. Toxic ASN-protein network and its effect on biological processes.…”

L‐DOPA regulates α‐synuclein accumulation in experimental parkinsonism

“…Remarkably, in the MPTP mouse model of PD, MPTP-induced tau hyperphosphorylation-which was α-synuclein-dependent -was found at Serine 396/404 [27]. Moreover, an increase in tau phosphorylation at Serine 202/Threonine 205, which might occur through GSK3β pathway, was also recently observed in the MPTP mouse model of PD in which phosphorylated tau and α-synuclein co-localised in SNpc and hippocampus and formed plaques in SNpc [48]. In contrast with this latter study, despite α-synuclein accumulation, we did not find significant increases in the density of phosphorylated tau PD brains [27], α-synuclein accumulation does not necessarily lead to phosphorylated tau accumulation and aggregation.…”

“…Moreover, tau is usually phosphorylated in LBs and NFTs [43][44][45]. Phosphorylation of tau at Threonine 231, Serine 202/Threonine 205 and Serine 396 has already been reported in Alzheimer disease [47,48]. Remarkably, in the MPTP mouse model of PD, MPTP-induced tau hyperphosphorylation-which was α-synuclein-dependent -was found at Serine 396/404 [27].…”