Phosphorylation and oligomerization of [alpha]-synuclein associated with GSK-3[beta] activation in the rTg4510 mouse model of tauopathy

• Published in: Acta neuropathologica communications 2020-06, Vol.8 (1)
• Main Authors: Takaichi, Yuta, Chambers, James K, Inoue, Hiroyuki, Ano, Yasuhisa, Takashima, Akihiko, Nakayama, Hiroyuki, Uchida, Kazuyuki
• Format: Article
• Language: English
• Subjects: EDTA; Immunohistochemistry; Nervous system diseases; Oligomers; Proteins
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-020-00969-8

Neurodegenerative diseases are characterized by the accumulation of specific phosphorylated protein aggregates in the brain, such as hyperphosphorylated tau (hp-tau) in tauopathies and phosphorylated [alpha]-synuclein (p-[alpha]Syn) in [alpha]-synucleinopathies. The simultaneous accumulation of different proteins is a common event in many neurodegenerative diseases. We herein describe the detection of the phosphorylation and dimerization of [alpha]Syn and activation of GSK-3[beta], a major kinase known to phosphorylate tau and [alpha]Syn, in the brains of rTg4510 mice that overexpress human P301L mutant tau. Immunohistochemistry showed p-[alpha]Syn aggregates in rTg4510 mice, which were suppressed by doxycycline-mediated decreases in mutant tau expression levels. A semi-quantitative analysis revealed a regional correlation between hp-tau and p-[alpha]Syn accumulation in rTg4510 mice. Furthermore, proteinase K-resistant [alpha]Syn aggregates were found in the region with excessive hp-tau accumulation in rTg4510 mice, and these aggregates were morphologically different from proteinase K-susceptible p-[alpha]Syn aggregates. Western blotting revealed decreases in p-[alpha]Syn monomers in TBS- and sarkosyl-soluble fractions and increases in ubiquitinated p-[alpha]Syn dimers in sarkosyl-soluble and insoluble fractions in rTg4510 mice. Furthermore, an activated form of GSK-3[beta] was immunohistochemically detected within cells containing both hp-tau and p-[alpha]Syn aggregates. A semi-quantitative analysis revealed that increased GSK-3[beta] activity strongly correlated with hp-tau and p-[alpha]Syn accumulation in rTg4510 mice. Collectively, the present results suggest that the overexpression of human P301L mutant tau promoted the phosphorylation and dimerization of endogenous [alpha]Syn by activating GSK-3[beta] in rTg4510 mice. This synergic effect between tau, [alpha]Syn, and GSK-3[beta] may be involved in the pathophysiology of several neurodegenerative diseases that show the accumulation of both tau and [alpha]Syn. Keywords: [alpha]-Synuclein, Tau, Phosphorylation, Oligomerization, GSK-3[beta], rTg4510