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Pathogenic LRRK2 compromises the subcellular distribution of lysosomes in a Rab12-RILPL1-dependent manner.
Ito, Kyohei; Araki, Miho; Katai, Yuta; Nishimura, Yuki; Imotani, Sota; Inoue, Haruki; Ito, Genta; Tomita, Taisuke.
Afiliación
  • Ito K; Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
  • Araki M; Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
  • Katai Y; HACARUS, Inc., Kyoto, Japan.
  • Nishimura Y; HACARUS, Inc., Kyoto, Japan.
  • Imotani S; HACARUS, Inc., Kyoto, Japan.
  • Inoue H; HACARUS, Inc., Kyoto, Japan.
  • Ito G; Department of Biomolecular Chemistry, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan.
  • Tomita T; Social Cooperation Program of Brain and Neurological Disorders, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
FASEB J ; 37(5): e22930, 2023 05.
Article en En | MEDLINE | ID: mdl-37086089
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson's disease (PD). Recent studies have shown that LRRK2 physiologically phosphorylates several Rab family proteins including Rab12 and that this phosphorylation is accelerated by the pathogenic mutations in LRRK2, although the significance in the PD pathogenesis remains unknown. Here we examined the effect of the overexpression of LRRK2 on the distribution of organelles in cultured cells and found that lysosomes become clustered in a perinuclear region upon the overexpression of pathogenic mutant LRRK2 in a manner dependent on its kinase activity. The perinuclear clustering of lysosomes was abolished by knocking out RAB12 as well as its effector protein RILPL1. Re-expression of Rab12 in RAB12 knockout cells suggested that the phosphorylation at Ser106 of Rab12 is required for the perinuclear clustering of lysosomes. Moreover, phosphorylated Rab12 was also accumulated on the clustered lysosomes, and the phosphorylation of Rab12 increased its interaction with RILPL1, leading us to conclude that the increase in the phosphorylation of Rab12 by pathogenic LRRK2 compromised intracellular lysosomal transport via the enhanced interaction of Rab12 with RILPL1. These data suggest the involvement of abnormal regulation of lysosomal transport in the LRRK2-mediated pathogenesis of PD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Unión al GTP rab / Proteínas Adaptadoras Transductoras de Señales / Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina / Lisosomas Límite: Humans Idioma: En Revista: FASEB J Asunto de la revista: BIOLOGIA / FISIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Unión al GTP rab / Proteínas Adaptadoras Transductoras de Señales / Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina / Lisosomas Límite: Humans Idioma: En Revista: FASEB J Asunto de la revista: BIOLOGIA / FISIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos