Abnormal localization of leucine-rich repeat kinase 2 to the endosomal-lysosomal compartment in lewy body disease

Shinji Higashi, Darren J. Moore, Ryoko Yamamoto, Michiko Minegishi, Kiyoshi Sato, Takashi Togo, Omi Katsuse, Hirotake Uchikado, Yoshiko Furukawa, Hiroaki Hino, Kenji Kosaka, Piers C. Emson, Keiji Wada, Valina L. Dawson, Ted M. Dawson, Heii Arai, Eizo Iseki

Research output: Contribution to journalArticlepeer-review


Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common causes of both familial and sporadic forms of Parkinson disease and are also associated with diverse pathological alterations. The mechanisms whereby LRRK2 mutations cause these pathological phenotypes are unknown. We used immunohistochemistry with 3 distinct anti-LRRK2 antibodies to characterize the expression of LRRK2 in the brains of 21 subjects with various neurodegenerative disorders and 7 controls. The immunoreactivity of LRRK2 was localized in a subset of brainstem-type Lewy bodies (LBs) but not in cortical-type LBs, tau-positive inclusions, or TARDNAYbinding protein-43Ypositive inclusions. The immunoreactivity of LRRK2 frequently appeared as enlarged granules or vacuoles within neurons of affected brain regions, including the substantia nigra, amygdala, and entorhinal cortex in patients with Parkinson disease or dementia with LBs. The volumes of LRRK2-positive granular structures in neurons of the entorhinal cortex were significantly increased in dementia with LBs brains compared with age-matched control brains (p G 0.05). Double immunolabeling demonstrated that these LRRK2-positive granular structures frequently colocalized with the late-endosomal marker Rab7B and occasionally with the lysosomal marker, the lysosomal-associated membrane protein 2. These results suggest that LRRK2 normally localizes to the endosomal-lysosomal compartment within morphologically altered neurons in neurodegenerative diseases, particularly in the brains of patients with LB diseases.

Original languageEnglish (US)
Pages (from-to)994-1005
Number of pages12
JournalJournal of neuropathology and experimental neurology
Issue number9
StatePublished - Sep 1 2009


  • Alzheimer disease
  • Dementia with Lewy bodies
  • Endosome
  • Leucine-rich repeat kinase 2
  • Lysosome
  • PARK8
  • Parkinson disease

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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