Phosphorylation and oligomerization of ?-synuclein associated with GSK-3? activation in the rTg4510 mouse model of tauopathy.

ABSTRACT: 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 ?-synuclein (p-?Syn) in ?-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 ?Syn and activation of GSK-3?, a major kinase known to phosphorylate tau and ?Syn, in the brains of rTg4510 mice that overexpress human P301L mutant tau. Immunohistochemistry showed p-?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-?Syn accumulation in rTg4510 mice. Furthermore, proteinase K-resistant ?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-?Syn aggregates. Western blotting revealed decreases in p-?Syn monomers in TBS- and sarkosyl-soluble fractions and increases in ubiquitinated p-?Syn dimers in sarkosyl-soluble and insoluble fractions in rTg4510 mice. Furthermore, an activated form of GSK-3? was immunohistochemically detected within cells containing both hp-tau and p-?Syn aggregates. A semi-quantitative analysis revealed that increased GSK-3? activity strongly correlated with hp-tau and p-?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 ?Syn by activating GSK-3? in rTg4510 mice. This synergic effect between tau, ?Syn, and GSK-3? may be involved in the pathophysiology of several neurodegenerative diseases that show the accumulation of both tau and ?Syn.

SUBMITTER: Takaichi Y 

PROVIDER: S-EPMC7304163 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature