title: Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known cause of Parkinson's disease (PD). Whether loss of LRRK2 function accounts for neurodegeneration of dopamine neurons in PD is not known, nor is it known whether LRRK2 kinase activity modulates the susceptibility of dopamine (DA) neurons to the selective dopaminergic toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To better understand the role of LRRK2 in DA neuronal survival and its role in the susceptibility of DA neurons to MPTP, we generated LRRK2 knock-out (KO) mice lacking the kinase domain of LRRK2. Here, we show that LRRK2 KO mice are viable and have no major abnormalities and live to adulthood. The dopaminergic system is normal in LRRK2 KO mice as assessed via HPLC for DA and its metabolites and via stereologic assessment of DA neuron number in young and aged mice. Importantly, there is no significant difference in the susceptibility of LRRK2 KO and wild-type mice to MPTP. These results suggest that LRRK2 plays little if any role in the development and survival of DA neurons under physiologic conditions. Thus, PD due to LRRK2 mutations are likely not due to a loss of function. Moreover, LRRK2 is not required for the susceptibility of DA neurons to MPTP.
authors.affiliation: Neuroregeneration Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Andres-Mateos
authors.forename: Rebeca
authors.initials: R
authors.lastname: Mejias
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sasaki
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Li
authors.forename: Brian M
authors.initials: BM
authors.lastname: Lin
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Rebecca
authors.initials: R
authors.lastname: Banerjee
authors.forename: Bobby
authors.initials: B
authors.lastname: Thomas
authors.forename: Lichuan
authors.initials: L
authors.lastname: Yang
authors.forename: Guosheng
authors.initials: G
authors.lastname: Liu
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D005260:Female; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D020267:MPTP Poisoning / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics*
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases