LRRK2 G2019S transgenic mice display increased susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity

Senthilkumar S. Karuppagounder, Yulan Xiong, Yunjong Lee, Maeve C. Lawless, Donghyun Kim, Emily Nordquist, Ian Martin, Preston Ge, Saurav Brahmachari, Aanishaa Jhaldiyal, Manoj Kumar, Shaida A. Andrabi, Ted M. Dawson, Valina L. Dawson

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of late onset autosomal dominant form of Parkinson disease (PD). Gain of kinase activity due to the substitution of Gly 2019 to Ser (G2019S) is the most common mutation in the kinase domain of LRRK2. Genetic predisposition and environmental toxins contribute to the susceptibility of neurodegeneration in PD. To identify whether the genetic mutations in LRRK2 increase the susceptibility to environmental toxins in PD models, we exposed transgenic mice expressing human G2019S mutant or wild type (WT) LRRK2 to the environmental toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP treatment resulted in a greater loss of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta (SNpc) in LRRK2 G2019S transgenic mice compared to the LRRK2 WT overexpressing mice. Similarly loss of dopamine levels were greater in the striatum of LRRK2 G2019S mice when compared to the LRRK2 WT mice when both were treated with MPTP. This study suggests a likely interaction between genetic and environmental risk factors in the PD pathogenesis and that the G2019S mutation in LRRK2 increases the susceptibility of dopamine neurons to PD-causing toxins.

Original languageEnglish (US)
JournalJournal of Chemical Neuroanatomy
DOIs
StateAccepted/In press - Oct 31 2015

Fingerprint

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Leucine
Transgenic Mice
Phosphotransferases
Parkinson Disease
Mutation
Dopaminergic Neurons
Tyrosine 3-Monooxygenase
Genetic Predisposition to Disease
Dopamine
Neurons

Keywords

  • Dopamine
  • Environmental factor
  • Genetic factor
  • LRRK2
  • MPTP
  • Parkinson's Disease
  • Stereology

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

LRRK2 G2019S transgenic mice display increased susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity. / Karuppagounder, Senthilkumar S.; Xiong, Yulan; Lee, Yunjong; Lawless, Maeve C.; Kim, Donghyun; Nordquist, Emily; Martin, Ian; Ge, Preston; Brahmachari, Saurav; Jhaldiyal, Aanishaa; Kumar, Manoj; Andrabi, Shaida A.; Dawson, Ted M.; Dawson, Valina L.

In: Journal of Chemical Neuroanatomy, 31.10.2015.

Research output: Contribution to journalArticle

Karuppagounder, SS, Xiong, Y, Lee, Y, Lawless, MC, Kim, D, Nordquist, E, Martin, I, Ge, P, Brahmachari, S, Jhaldiyal, A, Kumar, M, Andrabi, SA, Dawson, TM & Dawson, VL 2015, 'LRRK2 G2019S transgenic mice display increased susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity', Journal of Chemical Neuroanatomy. https://doi.org/10.1016/j.jchemneu.2016.01.007
Karuppagounder, Senthilkumar S. ; Xiong, Yulan ; Lee, Yunjong ; Lawless, Maeve C. ; Kim, Donghyun ; Nordquist, Emily ; Martin, Ian ; Ge, Preston ; Brahmachari, Saurav ; Jhaldiyal, Aanishaa ; Kumar, Manoj ; Andrabi, Shaida A. ; Dawson, Ted M. ; Dawson, Valina L. / LRRK2 G2019S transgenic mice display increased susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity. In: Journal of Chemical Neuroanatomy. 2015.
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abstract = "Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of late onset autosomal dominant form of Parkinson disease (PD). Gain of kinase activity due to the substitution of Gly 2019 to Ser (G2019S) is the most common mutation in the kinase domain of LRRK2. Genetic predisposition and environmental toxins contribute to the susceptibility of neurodegeneration in PD. To identify whether the genetic mutations in LRRK2 increase the susceptibility to environmental toxins in PD models, we exposed transgenic mice expressing human G2019S mutant or wild type (WT) LRRK2 to the environmental toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP treatment resulted in a greater loss of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta (SNpc) in LRRK2 G2019S transgenic mice compared to the LRRK2 WT overexpressing mice. Similarly loss of dopamine levels were greater in the striatum of LRRK2 G2019S mice when compared to the LRRK2 WT mice when both were treated with MPTP. This study suggests a likely interaction between genetic and environmental risk factors in the PD pathogenesis and that the G2019S mutation in LRRK2 increases the susceptibility of dopamine neurons to PD-causing toxins.",
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AU - Xiong, Yulan

AU - Lee, Yunjong

AU - Lawless, Maeve C.

AU - Kim, Donghyun

AU - Nordquist, Emily

AU - Martin, Ian

AU - Ge, Preston

AU - Brahmachari, Saurav

AU - Jhaldiyal, Aanishaa

AU - Kumar, Manoj

AU - Andrabi, Shaida A.

AU - Dawson, Ted M.

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AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of late onset autosomal dominant form of Parkinson disease (PD). Gain of kinase activity due to the substitution of Gly 2019 to Ser (G2019S) is the most common mutation in the kinase domain of LRRK2. Genetic predisposition and environmental toxins contribute to the susceptibility of neurodegeneration in PD. To identify whether the genetic mutations in LRRK2 increase the susceptibility to environmental toxins in PD models, we exposed transgenic mice expressing human G2019S mutant or wild type (WT) LRRK2 to the environmental toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP treatment resulted in a greater loss of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta (SNpc) in LRRK2 G2019S transgenic mice compared to the LRRK2 WT overexpressing mice. Similarly loss of dopamine levels were greater in the striatum of LRRK2 G2019S mice when compared to the LRRK2 WT mice when both were treated with MPTP. This study suggests a likely interaction between genetic and environmental risk factors in the PD pathogenesis and that the G2019S mutation in LRRK2 increases the susceptibility of dopamine neurons to PD-causing toxins.

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