Leucine-rich repeat kinase 2 is associated with the endoplasmic reticulum in dopaminergic neurons and accumulates in the core of Lewy bodies in Parkinson disease.
Mutation of the leucine-rich repeat kinase 2 (LRRK2) gene is the most frequent genetic cause of Parkinson disease (PD). To understand the role of LRRK2 in the neuropathology of PD, we investigated the protein expression in a healthy brain and brains from patients with PD and its subcellular localization in dopaminergic neurons. LRRK2 was found to be widely expressed in healthy adult brain, including areas involved in PD. By double fluorescent staining, we found that endogenous LRRK2 is colocalized with the endoplasmic reticulum (ER) markers Neurotrace and KDEL in human dopaminergic neurons. Labeling of brain sections with anti-LRRK2 and anti-α-synuclein antibodies revealed localization of LRRK2 in the core of 24% of Lewy bodies (LBs) in the substantia nigra and 11% of LBs in the locus coeruleus in idiopathic PD patients. The percentage was increased to 50% in both areas in a patient with the G2019S LRRK2 mutation. The finding of ER localization suggests the possibility that LRRK2 is involved in the ER stress response and could account for the susceptibility to neuronal degeneration of LRRK2 mutation carriers. The localization of LRRK2 protein in the core of a subset of LBs demonstrates the contribution of LRRK2 to LB formation and disease pathogenesis.
Vitte
Jérémie
J
Laboratory of Molecular Basis, Physiopathology and Treatment of Neurodegenerative Diseases, Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975, Paris, France.
Traver
Sabine
S
Maués De Paula
André
A
Lesage
Suzanne
S
Rovelli
Giorgio
G
Corti
Olga
O
Duyckaerts
Charles
C
Brice
Alexis
A
D000328:Adult; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D016631:Lewy Bodies / Q000201:enzymology*; D009474:Neurons / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine