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LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation.
Bae, Eun-Jin; Kim, Dong-Kyu; Kim, Changyoun; Mante, Michael; Adame, Anthony; Rockenstein, Edward; Ulusoy, Ayse; Klinkenberg, Michael; Jeong, Ga Ram; Bae, Jae Ryul; Lee, Cheolsoon; Lee, He-Jin; Lee, Byung-Dae; Di Monte, Donato A; Masliah, Eliezer; Lee, Seung-Jae.
Afiliación
  • Bae EJ; Departments of Biomedical Sciences and Medicine, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, Korea.
  • Kim DK; Departments of Biomedical Sciences and Medicine, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, Korea.
  • Kim C; Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Mante M; Department Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Adame A; Department Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Rockenstein E; Department Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Ulusoy A; Department Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Klinkenberg M; German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Strasse 27, 53127, Bonn, Germany.
  • Jeong GR; German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Strasse 27, 53127, Bonn, Germany.
  • Bae JR; Department of Neuroscience, Graduate School, Kyung Hee University, Seoul, 02447, Korea.
  • Lee C; Department of Neuroscience, Graduate School, Kyung Hee University, Seoul, 02447, Korea.
  • Lee HJ; Department of Anatomy, School of Medicine, Konkuk University, Seoul, 05029, Korea.
  • Lee BD; Department of Anatomy, School of Medicine, Konkuk University, Seoul, 05029, Korea.
  • Di Monte DA; Department of Physiology, School of Medicine, Kyung Hee University, Seoul, 02447, Korea.
  • Masliah E; German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Strasse 27, 53127, Bonn, Germany.
  • Lee SJ; Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Nat Commun ; 9(1): 3465, 2018 08 27.
Article en En | MEDLINE | ID: mdl-30150626
Propagation of α-synuclein aggregates has been suggested as a contributing factor in Parkinson's disease (PD) progression. However, the molecular mechanisms underlying α-synuclein aggregation are not fully understood. Here, we demonstrate in cell culture, nematode, and rodent models of PD that leucine-rich repeat kinase 2 (LRRK2), a PD-linked kinase, modulates α-synuclein propagation in a kinase activity-dependent manner. The PD-linked G2019S mutation in LRRK2, which increases kinase activity, enhances propagation efficiency. Furthermore, we show that the role of LRRK2 in α-synuclein propagation is mediated by RAB35 phosphorylation. Constitutive activation of RAB35 overrides the reduced α-synuclein propagation phenotype in lrk-1 mutant C. elegans. Finally, in a mouse model of synucleinopathy, administration of an LRRK2 kinase inhibitor reduced α-synuclein aggregation via enhanced interaction of α-synuclein with the lysosomal degradation pathway. These results suggest that LRRK2-mediated RAB35 phosphorylation is a potential therapeutic target for modifying disease progression.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plásmidos / Caenorhabditis elegans / Proteínas de Unión al GTP rab / Proteínas de Caenorhabditis elegans / Alfa-Sinucleína / Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2018 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plásmidos / Caenorhabditis elegans / Proteínas de Unión al GTP rab / Proteínas de Caenorhabditis elegans / Alfa-Sinucleína / Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2018 Tipo del documento: Article Pais de publicación: Reino Unido