title: Leucine-rich repeat kinase 2 (LRRK2) regulates α-synuclein clearance in microglia.
abstract: α-Synuclein (αSYN) has been genetically implicated in familial and sporadic Parkinson's disease (PD), and is associated with disease susceptibility, progression and pathology. Excess amounts of αSYN are toxic to neurons. In the brain, microglial αSYN clearance is closely related to neuronal survival. Leucine-rich repeat kinase 2 (LRRK2) is the one of the other genes implicated in familial and sporadic PD. While LRRK2 is known to be expressed in microglia, its true function remains to be elucidated. In this study, we investigated αSYN clearance by microglia isolated from LRRK2-knockout (KO) mice.
  
  
  
  In LRRK2-KO microglia, αSYN was taken up in larger amounts and cleared from the supernatant more effectively than for microglia isolated from wild-type (WT) mice. This higher clearance ability of LRRK2-KO microglia was thought to be due to an increase of Rab5-positive endosomes, but not Rab7- or Rab11-positive endosomes. Increased engagement between Rab5 and dynamin 1 was also observed in LRRK2-KO microglia.
  
  
  
  LRRK2 negatively regulates the clearance of αSYN accompanied by down-regulation of the endocytosis pathway. Our findings reveal a new functional role of LRRK2 in microglia and offer a new insight into the mechanism of PD pathogenesis.
authors.affiliation: Department of Biochemistry, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan. maekawa@kitasato-u.ac.jp.
authors.forename: Tatsunori
authors.identifier: 0000-0002-1214-9959
authors.initials: T
authors.lastname: Maekawa
authors.affiliation: Department of Laboratory Animal Science, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan.|Laboratory of Neurochemistry, National Institute for Basic Biology, 38 Nishigonaka Myodaiji, Okazaki, Aichi, 444-8585, Japan.|Department of Comparative and Experimental Medicine, Brain Research Institute, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8585, Japan.
authors.forename: Toshikuni
authors.initials: T
authors.lastname: Sasaoka
authors.affiliation: Department of Laboratory Animal Science, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan.
authors.forename: Sadahiro
authors.initials: S
authors.lastname: Azuma
authors.affiliation: Department of Biochemistry, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ichikawa
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL, 32224, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Melrose
authors.affiliation: Department of Medical Genetics, Centre for Applied Neurogenetics, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2329 West Mall, Vancouver, BC, V6T 1Z4, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
authors.affiliation: Division of Clinical Immunology, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan.|R & D Center for Cell Design, Institute for Regenerative Medicine and Cell Design, Kitasato University School of Allied Health Sciences, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan.
authors.forename: Fumiya
authors.initials: F
authors.lastname: Obata
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D034284:Dynamin I / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D011994:Recombinant Proteins / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; C497605:Snca protein, mouse; D051844:alpha-Synuclein; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D034284:Dynamin I; D020696:rab5 GTP-Binding Proteins
keywords: LRRK2; Microglia; α-Synuclein