| First Author | Takaichi Y | Year | 2020 |
| Journal | Acta Neuropathol Commun | Volume | 8 |
| Issue | 1 | Pages | 86 |
| PubMed ID | 32560668 | Mgi Jnum | J:319327 |
| Mgi Id | MGI:6863706 | Doi | 10.1186/s40478-020-00969-8 |
| Citation | Takaichi Y, et al. (2020) Phosphorylation and oligomerization of alpha-synuclein associated with GSK-3beta activation in the rTg4510 mouse model of tauopathy. Acta Neuropathol Commun 8(1):86 |
| abstractText | 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-alphaSyn) 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 alphaSyn and activation of GSK-3beta, a major kinase known to phosphorylate tau and alphaSyn, in the brains of rTg4510 mice that overexpress human P301L mutant tau. Immunohistochemistry showed p-alphaSyn 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-alphaSyn accumulation in rTg4510 mice. Furthermore, proteinase K-resistant alphaSyn 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-alphaSyn aggregates. Western blotting revealed decreases in p-alphaSyn monomers in TBS- and sarkosyl-soluble fractions and increases in ubiquitinated p-alphaSyn dimers in sarkosyl-soluble and insoluble fractions in rTg4510 mice. Furthermore, an activated form of GSK-3beta was immunohistochemically detected within cells containing both hp-tau and p-alphaSyn aggregates. A semi-quantitative analysis revealed that increased GSK-3beta activity strongly correlated with hp-tau and p-alphaSyn accumulation in rTg4510 mice. Collectively, the present results suggest that the overexpression of human P301L mutant tau promoted the phosphorylation and dimerization of endogenous alphaSyn by activating GSK-3beta in rTg4510 mice. This synergic effect between tau, alphaSyn, and GSK-3beta may be involved in the pathophysiology of several neurodegenerative diseases that show the accumulation of both tau and alphaSyn. |
