title: LRRK2 G2019S transgenic mice display increased susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity.
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.
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA.
authors.forename: Senthilkumar S
authors.initials: SS
authors.lastname: Karuppagounder
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA.
authors.forename: Yunjong
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Biological Science, Louisiana State University, Baton Rouge, LA 70803, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA.
authors.forename: Maeve C
authors.initials: MC
authors.lastname: Lawless
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Donghyun
authors.initials: D
authors.lastname: Kim
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Krieger School of Arts and Sciences, Department of Molecular and Cellular Biology, Johns Hopkins University, Baltimore MD 21218, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Nordquist
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Martin
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Krieger School of Arts and Sciences, Department of Molecular and Cellular Biology, Johns Hopkins University, Baltimore MD 21218, USA.
authors.forename: Preston
authors.initials: P
authors.lastname: Ge
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA.
authors.forename: Saurav
authors.initials: S
authors.lastname: Brahmachari
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA.
authors.forename: Aanishaa
authors.initials: A
authors.lastname: Jhaldiyal
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA.
authors.forename: Shaida A
authors.initials: SA
authors.lastname: Andrabi
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA. Electronic address: tdawson@jhmi.edu.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA. Electronic address: vdawson@jhmi.edu.
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
keywords: Dopamine; Environmental factor; Genetic factor; LRRK2; MPTP; Parkinson’s Disease; Stereology