PIKfyve activity is required for lysosomal trafficking of tau aggregates and tau seeding.
J Biol Chem
; 296: 100636, 2021.
Article
em En
| MEDLINE
| ID: mdl-33831417
ABSTRACT
Tauopathies, such as Alzheimer's disease (AD), are neurodegenerative disorders characterized by the deposition of hyperphosphorylated tau aggregates. Proteopathic tau seeds spread through the brain in a temporospatial pattern, indicative of transsynaptic propagation. It is hypothesized that reducing the uptake of tau seeds and subsequent induction of tau aggregation could be a potential approach for abrogating disease progression in AD. Here, we studied to what extent different endosomal routes play a role in the neuronal uptake of preformed tau seeds. Using pharmacological and genetic tools, we identified dynamin-1, actin, and Rac1 as key players. Furthermore, inhibition of PIKfyve, a protein downstream of Rac1, reduced both the trafficking of tau seeds into lysosomes and the induction of tau aggregation. Our work shows that tau aggregates are internalized by a specific endocytic mechanism and that their fate once internalized can be pharmacologically modulated to reduce tau seeding in neurons.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas tau
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Fosfatidilinositol 3-Quinases
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Tauopatias
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Agregação Patológica de Proteínas
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Hipocampo
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Lisossomos
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Neurônios
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article