Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aß<sub>1-42</sub> synaptotoxicity.

Qu, Xiaoyi; Yuan, Feng Ning; Corona, Carlo; Pasini, Silvia; Pero, Maria Elena; Gundersen, Gregg G; Shelanski, Michael L; Bartolini, Francesca

Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aß_1-42 synaptotoxicity.

Qu, Xiaoyi; Yuan, Feng Ning; Corona, Carlo; Pasini, Silvia; Pero, Maria Elena; Gundersen, Gregg G; Shelanski, Michael L; Bartolini, Francesca.

Afiliación

Qu X; Department of Pathology, Anatomy and Cell Biology, Columbia University, New York, NY.
Yuan FN; Department of Pathology, Anatomy and Cell Biology, Columbia University, New York, NY.
Corona C; Department of Pathology, Anatomy and Cell Biology, Columbia University, New York, NY.
Pasini S; Department of Pathology, Anatomy and Cell Biology, Columbia University, New York, NY.
Pero ME; Department of Pathology, Anatomy and Cell Biology, Columbia University, New York, NY.
Gundersen GG; Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy.
Shelanski ML; Department of Pathology, Anatomy and Cell Biology, Columbia University, New York, NY.
Bartolini F; Department of Pathology, Anatomy and Cell Biology, Columbia University, New York, NY.

J Cell Biol ; 216(10): 3161-3178, 2017 10 02.

Article en En | MEDLINE | ID: mdl-28877993

RESUMEN

Oligomeric Amyloid ß1-42 (Aß) plays a crucial synaptotoxic role in Alzheimer's disease, and hyperphosphorylated tau facilitates Aß toxicity. The link between Aß and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Aß acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corrects the synaptotoxicity and deficits of axonal transport induced by Aß. We explored the mechanism of rescue and found that stabilization of dynamic MTs promotes tau-dependent loss of dendritic spines and tau hyperphosphorylation. Collectively, these results uncover a novel role for mDia1 in Aß-mediated synaptotoxicity and demonstrate that inhibition of MT dynamics and accumulation of PTMs are driving factors for the induction of tau-mediated neuronal damage.

Asunto(s)

Péptidos beta-Amiloides/metabolismo; Axones/metabolismo; Proteínas Portadoras/metabolismo; Citocromo-B(5) Reductasa/metabolismo; Espinas Dendríticas/metabolismo; Microtúbulos/metabolismo; Fragmentos de Péptidos/metabolismo; Sinapsis/metabolismo; Proteínas tau/metabolismo; Enfermedad de Alzheimer/genética; Enfermedad de Alzheimer/metabolismo; Péptidos beta-Amiloides/genética; Animales; Proteínas Portadoras/genética; Citocromo-B(5) Reductasa/genética; Forminas; Ratones; Ratones Noqueados; Microtúbulos/genética; Fragmentos de Péptidos/genética; Procesamiento Proteico-Postraduccional/genética; Transporte de Proteínas/genética; Ratas; Ratas Sprague-Dawley; Sinapsis/genética; Proteínas tau/genética

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fragmentos de Péptidos / Axones / Sinapsis / Proteínas Portadoras / Péptidos beta-Amiloides / Proteínas tau / Citocromo-B(5) Reductasa / Espinas Dendríticas / Microtúbulos Límite: Animals Idioma: En Revista: J Cell Biol Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos

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