Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice

Yulan Xiong, Stewart Neifert, Senthilkumar Karuppagounder, Qinfang Liu, Jeannette N. Stankowski, Byoung Dae Lee, Hanseok Seok Ko, Yunjong Lee, Jonathan C. Grima, Xiaobo Mao, Haisong Jiang, SungUng Kang, Deborah A. Swing, Lorraine Iacovitti, Lino Tessarollo, Ted M Dawson, Valina Dawson

Research output: Contribution to journalArticle

Abstract

Mutations in LRRK2 are known to be the most common genetic cause of sporadic and familial Parkinson’s disease (PD). Multiple lines of LRRK2 transgenic or knockin mice have been developed, yet none exhibit substantial dopamine (DA)-neuron degeneration. Here we develop human tyrosine hydroxylase (TH) promoter-controlled tetracycline-sensitive LRRK2 G2019S (GS) and LRRK2 G2019S kinase-dead (GS/DA) transgenic mice and show that LRRK2 GS expression leads to an age- and kinase-dependent cell-autonomous neurodegeneration of DA and norepinephrine (NE) neurons. Accompanying the loss of DA neurons are DA-dependent behavioral deficits and α-synuclein pathology that are also LRRK2 GS kinase-dependent. Transmission EM reveals that that there is an LRRK2 GS kinase-dependent significant reduction in synaptic vesicle number and a greater abundance of clathrin-coated vesicles in DA neurons. These transgenic mice indicate that LRRK2-induced DA and NE neurodegeneration is kinase-dependent and can occur in a cell-autonomous manner. Moreover, these mice provide a substantial advance in animal model development for LRRK2-associated PD and an important platform to investigate molecular mechanisms for how DA neurons degenerate as a result of expression of mutant LRRK2.

Original languageEnglish (US)
Pages (from-to)1635-1640
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number7
DOIs
StatePublished - Feb 13 2018

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Dopaminergic Neurons
Transgenic Mice
Norepinephrine
Phosphotransferases
Parkinson Disease
Dopamine
Synucleins
Clathrin-Coated Vesicles
Nerve Degeneration
Synaptic Vesicles
Tyrosine 3-Monooxygenase
Tetracycline
Animal Models
Pathology
Mutation

Keywords

  • LRRK2
  • Neurodegeneration
  • Parkinson’s disease
  • Α-synuclein

ASJC Scopus subject areas

  • General

Cite this

Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice. / Xiong, Yulan; Neifert, Stewart; Karuppagounder, Senthilkumar; Liu, Qinfang; Stankowski, Jeannette N.; Lee, Byoung Dae; Ko, Hanseok Seok; Lee, Yunjong; Grima, Jonathan C.; Mao, Xiaobo; Jiang, Haisong; Kang, SungUng; Swing, Deborah A.; Iacovitti, Lorraine; Tessarollo, Lino; Dawson, Ted M; Dawson, Valina.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 7, 13.02.2018, p. 1635-1640.

Research output: Contribution to journalArticle

Xiong, Yulan ; Neifert, Stewart ; Karuppagounder, Senthilkumar ; Liu, Qinfang ; Stankowski, Jeannette N. ; Lee, Byoung Dae ; Ko, Hanseok Seok ; Lee, Yunjong ; Grima, Jonathan C. ; Mao, Xiaobo ; Jiang, Haisong ; Kang, SungUng ; Swing, Deborah A. ; Iacovitti, Lorraine ; Tessarollo, Lino ; Dawson, Ted M ; Dawson, Valina. / Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 7. pp. 1635-1640.
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AU - Neifert, Stewart

AU - Karuppagounder, Senthilkumar

AU - Liu, Qinfang

AU - Stankowski, Jeannette N.

AU - Lee, Byoung Dae

AU - Ko, Hanseok Seok

AU - Lee, Yunjong

AU - Grima, Jonathan C.

AU - Mao, Xiaobo

AU - Jiang, Haisong

AU - Kang, SungUng

AU - Swing, Deborah A.

AU - Iacovitti, Lorraine

AU - Tessarollo, Lino

AU - Dawson, Ted M

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N2 - Mutations in LRRK2 are known to be the most common genetic cause of sporadic and familial Parkinson’s disease (PD). Multiple lines of LRRK2 transgenic or knockin mice have been developed, yet none exhibit substantial dopamine (DA)-neuron degeneration. Here we develop human tyrosine hydroxylase (TH) promoter-controlled tetracycline-sensitive LRRK2 G2019S (GS) and LRRK2 G2019S kinase-dead (GS/DA) transgenic mice and show that LRRK2 GS expression leads to an age- and kinase-dependent cell-autonomous neurodegeneration of DA and norepinephrine (NE) neurons. Accompanying the loss of DA neurons are DA-dependent behavioral deficits and α-synuclein pathology that are also LRRK2 GS kinase-dependent. Transmission EM reveals that that there is an LRRK2 GS kinase-dependent significant reduction in synaptic vesicle number and a greater abundance of clathrin-coated vesicles in DA neurons. These transgenic mice indicate that LRRK2-induced DA and NE neurodegeneration is kinase-dependent and can occur in a cell-autonomous manner. Moreover, these mice provide a substantial advance in animal model development for LRRK2-associated PD and an important platform to investigate molecular mechanisms for how DA neurons degenerate as a result of expression of mutant LRRK2.

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