(R1441C) LRRK2 induces the degeneration of SN dopaminergic neurons and alters the expression of genes regulating neuronal survival in a transgenic mouse model

Yi-Hsin Weng; Chu-Yu Chen; Kun-Jun Lin; Ying-Ling Chen; Tu-Hsueh Yeh; Ing-Tsung Hsiao; Ing-Jou Chen; Chin-Song Lu; Hung-Li Wang

doi:10.1016/j.expneurol.2015.09.001

(R1441C) LRRK2 induces the degeneration of SN dopaminergic neurons and alters the expression of genes regulating neuronal survival in a transgenic mouse model

Exp Neurol. 2016 Jan:275 Pt 1:104-15. doi: 10.1016/j.expneurol.2015.09.001. Epub 2015 Sep 10.

Authors

Yi-Hsin Weng¹, Chu-Yu Chen², Kun-Jun Lin³, Ying-Ling Chen⁴, Tu-Hsueh Yeh⁵, Ing-Tsung Hsiao⁶, Ing-Jou Chen⁷, Chin-Song Lu⁸, Hung-Li Wang⁹

Affiliations

¹ 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.
² Department of Physiology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.
³ 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.
⁴ Chang Gung University of Science and Technology, Taoyuan, Taiwan, ROC.
⁵ Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC.
⁶ 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.
⁷ Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan, ROC.
⁸ 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.
⁹ 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.

PMID: 26363496
DOI: 10.1016/j.expneurol.2015.09.001

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.

Keywords: (R1441C) LRRK2; Microarray; Parkinson's disease; Transgenic mice.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Survival / genetics*
Dopaminergic Neurons / metabolism*
Dopaminergic Neurons / pathology
Gene Expression Regulation*
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Levodopa / pharmacology
Mice
Mice, Transgenic
Motor Activity / drug effects
Motor Activity / genetics
Nerve Degeneration / genetics
Nerve Degeneration / metabolism*
Nerve Degeneration / pathology
Neurogenesis / genetics
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Substantia Nigra / metabolism*
Substantia Nigra / pathology

Substances

Levodopa
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Lrrk2 protein, mouse
Protein Serine-Threonine Kinases