Your browser doesn't support javascript.
loading
LRP1 is a master regulator of tau uptake and spread.
Rauch, Jennifer N; Luna, Gabriel; Guzman, Elmer; Audouard, Morgane; Challis, Collin; Sibih, Youssef E; Leshuk, Carolina; Hernandez, Israel; Wegmann, Susanne; Hyman, Bradley T; Gradinaru, Viviana; Kampmann, Martin; Kosik, Kenneth S.
Afiliação
  • Rauch JN; Neuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA.
  • Luna G; Neuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA.
  • Guzman E; Neuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA.
  • Audouard M; Neuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA.
  • Challis C; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
  • Sibih YE; Neuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA.
  • Leshuk C; Neuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA.
  • Hernandez I; Neuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA.
  • Wegmann S; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
  • Hyman BT; Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Gradinaru V; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
  • Kampmann M; Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, The California Institute for Quantitative Biomedical Research, Quantitative Biosciences Institute, University of California, San Francisco, CA, USA.
  • Kosik KS; Chan Zuckerberg Biohub, San Francisco, CA, USA.
Nature ; 580(7803): 381-385, 2020 04.
Article em En | MEDLINE | ID: mdl-32296178
The spread of protein aggregates during disease progression is a common theme underlying many neurodegenerative diseases. The microtubule-associated protein tau has a central role in the pathogenesis of several forms of dementia known as tauopathies-including Alzheimer's disease, frontotemporal dementia and chronic traumatic encephalopathy1. Progression of these diseases is characterized by the sequential spread and deposition of protein aggregates in a predictable pattern that correlates with clinical severity2. This observation and complementary experimental studies3,4 have suggested that tau can spread in a prion-like manner, by passing to naive cells in which it templates misfolding and aggregation. However, although the propagation of tau has been extensively studied, the underlying cellular mechanisms remain poorly understood. Here we show that the low-density lipoprotein receptor-related protein 1 (LRP1) controls the endocytosis of tau and its subsequent spread. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and in induced pluripotent stem cell-derived neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule-binding repeat region of tau. Furthermore, downregulation of LRP1 in an in vivo mouse model of tau spread was found to effectively reduce the propagation of tau between neurons. Our results identify LRP1 as a key regulator of tau spread in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas tau / Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: Nature Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas tau / Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: Nature Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos