title: (R1441C) LRRK2 induces the degeneration of SN dopaminergic neurons and alters the expression of genes regulating neuronal survival in a transgenic mouse model.
abstract: Mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Several mutations in LRRK2 gene were reported in PD patients. R1441 is the second most frequent site of LRRK2 mutation. We generated (R1441C) LRRK2 transgenic mice that displayed motor deficits at the age of 16 months. Compared with wild-type mice, 16-month-old (R1441C) LRRK2 mice exhibited a significant reduction in the number of substantia nigra (SN) dopaminergic neurons. To elucidate molecular pathogenic pathways involved in (R1441C) LRRK2-induced death of SN dopaminergic neurons, we performed microarray analysis to visualize altered mRNA expressions in the SN of (R1441C) LRRK2 mouse. In the SN of (R1441C) LRRK2 transgenic mouse, the mRNA expression of three genes that promote cell death was upregulated, while the mRNA expression of seven genes that contribute to neurogenesis/neuroprotection was significantly downregulated. Our results suggest that altered expression of these genes involved in regulating neuronal survival may contribute to the pathogenesis of (R1441C) LRRK2-induced PD.
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC; Graduate Institute of Clinical Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Weng
authors.affiliation: Department of Physiology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.
authors.forename: Chu-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Department of Nuclear Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC.
authors.forename: Kun-Jun
authors.initials: KJ
authors.lastname: Lin
authors.affiliation: Chang Gung University of Science and Technology, Taoyuan, Taiwan, ROC.
authors.forename: Ying-Ling
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC.
authors.forename: Tu-Hsueh
authors.initials: TH
authors.lastname: Yeh
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan, ROC.
authors.forename: Ing-Tsung
authors.initials: IT
authors.lastname: Hsiao
authors.affiliation: Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan, ROC.
authors.forename: Ing-Jou
authors.initials: IJ
authors.lastname: Chen
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan, ROC.
authors.forename: Chin-Song
authors.initials: CS
authors.lastname: Lu
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Department of Physiology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan, ROC. Electronic address: hlwns@mail.cgu.edu.tw.
authors.forename: Hung-Li
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics*; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D007980:Levodopa / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055495:Neurogenesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology
chemical_list: D007980:Levodopa; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: (R1441C) LRRK2; Microarray; Parkinson's disease; Transgenic mice