학술논문
Cytoplasmic aggregation of TDP43 and topographic correlation with tau and α-synuclein accumulation in the rTg4510 mouse model of tauopathy.
Document Type
Academic Journal
Author
Nakayama Y; Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Science, The University of Tokyo, Tokyo, Japan.; Chambers JK; Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Science, The University of Tokyo, Tokyo, Japan.; Takaichi Y; Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Science, The University of Tokyo, Tokyo, Japan.; Uchida K; Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Science, The University of Tokyo, Tokyo, Japan.
Source
Publisher: Oxford University Press Country of Publication: England NLM ID: 2985192R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-6578 (Electronic) Linking ISSN: 00223069 NLM ISO Abbreviation: J Neuropathol Exp Neurol Subsets: MEDLINE
Subject
Language
English
Abstract
In patients with TDP43 proteinopathy, phosphorylated TDP43 (p-TDP43) accumulates in the cytoplasm of neurons. The accumulation of p-TDP43 has also been reported in patients with tauopathy and α-synucleinopathy. We investigated spatiotemporal changes in p-TDP43 accumulation in the brains of rTg4510 mice that overexpressed human mutant tau (P301L) and exhibited hyperphosphorylated tau (hp-tau) and phosphorylated αSyn (p-αSyn) accumulation. Immunohistochemically, p-TDP43 aggregates were observed in the cytoplasm of neurons, which increased with age. A significant positive correlation was observed between the number of cells with p-TDP43 aggregates and hp-tau and p-αSyn aggregates. Suppression of the human mutant tau (P301L) expression by doxycycline treatment reduces the accumulation of p-TDP43, hp-tau, and p-αSyn. Proteinase K-resistant p-TDP43 aggregates were found in regions with high hp-tau, and p-αSyn accumulation. Western blotting of the sarkosyl-insoluble fraction revealed bands of monomeric TDP43 and p-TDP43. These results indicate that the accumulation of mouse p-TDP43 is associated with the accumulation of human mutant tau (P301L) in rTg4510 mouse brains. The accumulation of hp-tau and p-αSyn may promote sarkosyl-insoluble p-TDP43 aggregates that are resistant to proteinase K. The synergistic effects of tau, TDP43, and αSyn may be involved in the pathology of proteinopathies, leading to the accumulation of multiple abnormal proteins.
(© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
(© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)