Cytoplasmic aggregation of TDP43 and topographic correlation with tau and &#945;-synuclein accumulation in the rTg4510 mouse model of tauopathy.

Nakayama, Yutaro; Chambers, James K; Takaichi, Yuta; Uchida, Kazuyuki

Cytoplasmic aggregation of TDP43 and topographic correlation with tau and α-synuclein accumulation in the rTg4510 mouse model of tauopathy.

Nakayama, Yutaro; Chambers, James K; Takaichi, Yuta; Uchida, Kazuyuki.

Afiliación

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.

J Neuropathol Exp Neurol ; 83(10): 833-842, 2024 Oct 01.

Article en En | MEDLINE | ID: mdl-38879441

ABSTRACT

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.

Asunto(s)

Citoplasma; Proteínas de Unión al ADN; Modelos Animales de Enfermedad; Ratones Transgénicos; Tauopatías; alfa-Sinucleína; Proteínas tau; Animales; alfa-Sinucleína/metabolismo; alfa-Sinucleína/genética; Proteínas tau/metabolismo; Proteínas tau/genética; Tauopatías/patología; Tauopatías/metabolismo; Tauopatías/genética; Proteínas de Unión al ADN/metabolismo; Proteínas de Unión al ADN/genética; Ratones; Humanos; Citoplasma/metabolismo; Encéfalo/metabolismo; Encéfalo/patología; Fosforilación; Neuronas/metabolismo; Neuronas/patología

Palabras clave

TDP43; Tau; proteinopathy; rTg4510; α-synuclein

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ratones Transgénicos / Proteínas tau / Tauopatías / Citoplasma / Modelos Animales de Enfermedad / Proteínas de Unión al ADN / Alfa-Sinucleína Límite: Animals / Humans Idioma: En Revista: J Neuropathol Exp Neurol Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google