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

Journal of Chemical Neuroanatomy
Senthilkumar S KaruppagounderValina L Dawson

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.

References

May 11, 1992·Annals of the New York Academy of Sciences·D A Di MonteJ W Langston
Jun 24, 1998·Clinical Neurology and Neurosurgery·B A VeldmanM W Horstink
Jun 28, 2002·Physiological Reviews·Mark P MattsonWenzhen Duan
Nov 14, 2002·Neurotoxicology·Donato A Di MonteAmy B Manning-Bog
Aug 28, 2003·Experimental and Toxicologic Pathology : Official Journal of the Gesellschaft Für Toxikologische Pathologie·Tim KarlStephan von Hörsten
Jan 18, 2005·Neuroscience·C Schmitz, P R Hof
Jul 11, 2006·The Journal of Clinical Investigation·Joseph M SavittTed M Dawson
Sep 19, 2006·Nature Neuroscience·Wanli W SmithChristopher A Ross
Oct 25, 2006·Neurology·A RajputM J Farrer
Apr 3, 2007·Nature Protocols·Vernice Jackson-Lewis, Serge Przedborski
Jun 16, 2009·Lancet·Andrew J LeesTamas Revesz
Jul 25, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Shamol SahaBenjamin Wolozin
Sep 11, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Chee-Hoe NgKah-Leong Lim
Dec 18, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Eva Andres-MateosValina L Dawson
Apr 14, 2010·PLoS Genetics·Yulan XiongDarren J Moore
Jun 16, 2010·Neuron·Ted M DawsonValina L Dawson
Feb 15, 2012·Neurochemical Research·Senthilkumar S KaruppagounderMuralikrishanan Dhanasekaran
Mar 17, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Yulan XiongValina L Dawson

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Citations

Feb 2, 2018·Proceedings of the National Academy of Sciences of the United States of America·Yulan XiongValina L Dawson
Nov 7, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Xia LeiG William Wong
Jun 9, 2019·Journal of Neuroinflammation·Chris RudykUNKNOWN CLINT membership
May 3, 2018·Frontiers in Aging Neuroscience·Xian-Si ZengPeng-Peng Zhang
Jun 12, 2020·Frontiers in Neuroscience·Marta MadureiraRichard Wade-Martins
Jan 11, 2020·Frontiers in Neuroscience·Federica AlbaneseMichele Morari
Jul 7, 2020·Frontiers in Neuroscience·Darren M O'HaraLorraine V Kalia
Apr 19, 2017·Current Environmental Health Reports·Sheila M Fleming
Mar 16, 2017·Acta Neuropathologica Communications·Francesco LongoMichele Morari
Dec 23, 2019·Molecular Neurodegeneration·Daniel C BerwickKirsten Harvey
Sep 26, 2019·Frontiers in Human Neuroscience·Chao RenPeiyuan Yin
Jan 12, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Gabriella MacDougallOrnit Chiba-Falek
Jan 27, 2021·International Journal of Molecular Sciences·Vinita G Chittoor-VinodBirgitt Schüle
Mar 26, 2021·Neurotoxicity Research·Mohamed El-GamalAhmed A Moustafa
Apr 4, 2021·Genes·Eun-Mi Hur, Byoung Dae Lee
May 19, 2021·Neurochemistry International·Senthilkumar S KaruppagounderMuralikrishnan Dhanasekaran
Oct 15, 2021·Journal of Neuroinflammation·Shawn Hayley, Hongyu Sun

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