Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

Eva Andres-Mateos, Rebeca Mejias, Masayuki Sasaki, Xiaojie Li, Brian M. Lin, Saskia Biskup, Li Zhang, Rebecca Banerjee, Bobby Thomas, Lichuan Yang, Guosheng Liu, M. Flint Beal, David L. Huso, Ted M. Dawson, Valina L. Dawson

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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.

Original languageEnglish (US)
Pages (from-to)15846-15850
Number of pages5
JournalJournal of Neuroscience
Volume29
Issue number50
DOIs
StatePublished - Dec 16 2009

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Knockout Mice
Leucine
Hypersensitivity
Phosphotransferases
Dopaminergic Neurons
Parkinson Disease
Dopamine
Mutation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Andres-Mateos, E., Mejias, R., Sasaki, M., Li, X., Lin, B. M., Biskup, S., ... Dawson, V. L. (2009). Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Journal of Neuroscience, 29(50), 15846-15850. https://doi.org/10.1523/JNEUROSCI.4357-09.2009

Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). / Andres-Mateos, Eva; Mejias, Rebeca; Sasaki, Masayuki; Li, Xiaojie; Lin, Brian M.; Biskup, Saskia; Zhang, Li; Banerjee, Rebecca; Thomas, Bobby; Yang, Lichuan; Liu, Guosheng; Beal, M. Flint; Huso, David L.; Dawson, Ted M.; Dawson, Valina L.

In: Journal of Neuroscience, Vol. 29, No. 50, 16.12.2009, p. 15846-15850.

Research output: Contribution to journalArticle

Andres-Mateos, E, Mejias, R, Sasaki, M, Li, X, Lin, BM, Biskup, S, Zhang, L, Banerjee, R, Thomas, B, Yang, L, Liu, G, Beal, MF, Huso, DL, Dawson, TM & Dawson, VL 2009, 'Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)', Journal of Neuroscience, vol. 29, no. 50, pp. 15846-15850. https://doi.org/10.1523/JNEUROSCI.4357-09.2009
Andres-Mateos, Eva ; Mejias, Rebeca ; Sasaki, Masayuki ; Li, Xiaojie ; Lin, Brian M. ; Biskup, Saskia ; Zhang, Li ; Banerjee, Rebecca ; Thomas, Bobby ; Yang, Lichuan ; Liu, Guosheng ; Beal, M. Flint ; Huso, David L. ; Dawson, Ted M. ; Dawson, Valina L. / Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In: Journal of Neuroscience. 2009 ; Vol. 29, No. 50. pp. 15846-15850.
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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.",
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AU - Andres-Mateos, Eva

AU - Mejias, Rebeca

AU - Sasaki, Masayuki

AU - Li, Xiaojie

AU - Lin, Brian M.

AU - Biskup, Saskia

AU - Zhang, Li

AU - Banerjee, Rebecca

AU - Thomas, Bobby

AU - Yang, Lichuan

AU - Liu, Guosheng

AU - Beal, M. Flint

AU - Huso, David L.

AU - Dawson, Ted M.

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