Phosphorylation and oligomerization of α-synuclein associated with GSK-3β 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 α-synuclein (p-αSyn) in α-synucleinopathies. The simultaneous accumulation of different pro...
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doaj-c8b159b325814c69a422f1aa5c3eb3d52020-11-25T03:59:22ZengBMCActa Neuropathologica Communications2051-59602020-06-018111410.1186/s40478-020-00969-8Phosphorylation and oligomerization of α-synuclein associated with GSK-3β activation in the rTg4510 mouse model of tauopathyYuta Takaichi0James K. Chambers1Hiroyuki Inoue2Yasuhisa Ano3Akihiko Takashima4Hiroyuki Nakayama5Kazuyuki Uchida6Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of TokyoLaboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of TokyoLaboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of TokyoResearch Laboratories for Health Science & Food Technologies and the Central Laboratories for Key Technologies, Kirin Company Ltd.Department of Life Science, Faculty of Science, Gakushuin UniversityLaboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of TokyoLaboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of TokyoAbstract 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 α-synuclein (p-αSyn) in α-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 αSyn and activation of GSK-3β, a major kinase known to phosphorylate tau and αSyn, in the brains of rTg4510 mice that overexpress human P301L mutant tau. Immunohistochemistry showed p-αSyn 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-αSyn accumulation in rTg4510 mice. Furthermore, proteinase K-resistant αSyn 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-αSyn aggregates. Western blotting revealed decreases in p-αSyn monomers in TBS- and sarkosyl-soluble fractions and increases in ubiquitinated p-αSyn dimers in sarkosyl-soluble and insoluble fractions in rTg4510 mice. Furthermore, an activated form of GSK-3β was immunohistochemically detected within cells containing both hp-tau and p-αSyn aggregates. A semi-quantitative analysis revealed that increased GSK-3β activity strongly correlated with hp-tau and p-αSyn accumulation in rTg4510 mice. Collectively, the present results suggest that the overexpression of human P301L mutant tau promoted the phosphorylation and dimerization of endogenous αSyn by activating GSK-3β in rTg4510 mice. This synergic effect between tau, αSyn, and GSK-3β may be involved in the pathophysiology of several neurodegenerative diseases that show the accumulation of both tau and αSyn.http://link.springer.com/article/10.1186/s40478-020-00969-8α-SynucleinTauPhosphorylationOligomerizationGSK-3βrTg4510 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yuta Takaichi James K. Chambers Hiroyuki Inoue Yasuhisa Ano Akihiko Takashima Hiroyuki Nakayama Kazuyuki Uchida |
spellingShingle |
Yuta Takaichi James K. Chambers Hiroyuki Inoue Yasuhisa Ano Akihiko Takashima Hiroyuki Nakayama Kazuyuki Uchida Phosphorylation and oligomerization of α-synuclein associated with GSK-3β activation in the rTg4510 mouse model of tauopathy Acta Neuropathologica Communications α-Synuclein Tau Phosphorylation Oligomerization GSK-3β rTg4510 |
author_facet |
Yuta Takaichi James K. Chambers Hiroyuki Inoue Yasuhisa Ano Akihiko Takashima Hiroyuki Nakayama Kazuyuki Uchida |
author_sort |
Yuta Takaichi |
title |
Phosphorylation and oligomerization of α-synuclein associated with GSK-3β activation in the rTg4510 mouse model of tauopathy |
title_short |
Phosphorylation and oligomerization of α-synuclein associated with GSK-3β activation in the rTg4510 mouse model of tauopathy |
title_full |
Phosphorylation and oligomerization of α-synuclein associated with GSK-3β activation in the rTg4510 mouse model of tauopathy |
title_fullStr |
Phosphorylation and oligomerization of α-synuclein associated with GSK-3β activation in the rTg4510 mouse model of tauopathy |
title_full_unstemmed |
Phosphorylation and oligomerization of α-synuclein associated with GSK-3β activation in the rTg4510 mouse model of tauopathy |
title_sort |
phosphorylation and oligomerization of α-synuclein associated with gsk-3β activation in the rtg4510 mouse model of tauopathy |
publisher |
BMC |
series |
Acta Neuropathologica Communications |
issn |
2051-5960 |
publishDate |
2020-06-01 |
description |
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 α-synuclein (p-αSyn) in α-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 αSyn and activation of GSK-3β, a major kinase known to phosphorylate tau and αSyn, in the brains of rTg4510 mice that overexpress human P301L mutant tau. Immunohistochemistry showed p-αSyn 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-αSyn accumulation in rTg4510 mice. Furthermore, proteinase K-resistant αSyn 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-αSyn aggregates. Western blotting revealed decreases in p-αSyn monomers in TBS- and sarkosyl-soluble fractions and increases in ubiquitinated p-αSyn dimers in sarkosyl-soluble and insoluble fractions in rTg4510 mice. Furthermore, an activated form of GSK-3β was immunohistochemically detected within cells containing both hp-tau and p-αSyn aggregates. A semi-quantitative analysis revealed that increased GSK-3β activity strongly correlated with hp-tau and p-αSyn accumulation in rTg4510 mice. Collectively, the present results suggest that the overexpression of human P301L mutant tau promoted the phosphorylation and dimerization of endogenous αSyn by activating GSK-3β in rTg4510 mice. This synergic effect between tau, αSyn, and GSK-3β may be involved in the pathophysiology of several neurodegenerative diseases that show the accumulation of both tau and αSyn. |
topic |
α-Synuclein Tau Phosphorylation Oligomerization GSK-3β rTg4510 |
url |
http://link.springer.com/article/10.1186/s40478-020-00969-8 |
work_keys_str_mv |
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