Overexpression of Parkinson's Disease-Associated Mutation LRRK2 G2019S in Mouse Forebrain Induces Behavioral Deficits and α-Synuclein Pathology.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as an unambiguous cause of late-onset, autosomal-dominant familial Parkinson's disease (PD) and LRRK2 mutations are the strongest genetic risk factor for sporadic PD known to date. A number of transgenic mice expressing wild-type or mutant LRRK2 have been described with varying degrees of LRRK2-related abnormalities and modest pathologies. None of these studies directly addressed the role of the kinase domain in the changes observed and none of the mice present with robust features of the human disease. In an attempt to address these issues, we created a conditional LRRK2 G2019S (LRRK2 GS) mutant and a functionally negative control, LRRK2 G2019S/D1994A (LRRK2 GS/DA). Expression of LRRK2 GS or LRRK2 GS/DA was conditionally controlled using the tet-off system in which the presence of tetracycline-transactivator protein (tTA) with a CAMKIIαpromoter (CAMKIIα-tTA) induced expression of TetP-LRRK2 GS or TetP-LRRK2 GS/DA in the mouse forebrain. Overexpression of LRRK2 GS in mouse forebrain induced behavioral deficits and α-synuclein pathology in a kinase-dependent manner. Similar to other genetically engineered LRRK2 GS mice, there was no significant loss of dopaminergic neurons. These mice provide an important new tool to study neurobiological changes associated with the increased kinase activity from the LRRK2 G2019S mutation, which may ultimately lead to a better understanding of not only the physiologic actions of LRRK2, but also potential pathologic actions that underlie LRRK2 GS-associated PD.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Anatomy and Physiology, Kansas State University College of Veterinary Medicine, Manhattan, Kansas 66506.
Yulan
0000-0003-1649-7552
Y
Xiong
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Stewart
0000-0001-5389-347X
S
Neifert
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Senthilkumar S
0000-0002-3281-9913
SS
Karuppagounder
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Jeannette N
0000-0002-8481-2940
JN
Stankowski
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Byoung Dae
0000-0003-0182-2279
BD
Lee
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Soloman H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Jonathan C
JC
Grima
Department of Anatomy and Physiology, Kansas State University College of Veterinary Medicine , Manhattan, Kansas 66506.
Guanxing
G
Chen
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Han Seok
0000-0002-0864-5239
HS
Ko
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Yunjong
0000-0003-0182-2279
Y
Lee
Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute , Frederick, Maryland 21702.
Debbie
D
Swing
Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute , Frederick, Maryland 21702.
Lino
L
Tessarollo
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Soloman H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130.
Ted M
0000-0002-6459-0893
TM
Dawson
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Soloman H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130.
Valina L
0000-0002-2915-3970
VL
Dawson
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology* / Q000523:psychology; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D066263:Protein Aggregation, Pathological / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
D000697:Central Nervous System Stimulants; C497605:Snca protein, mouse; D051844:alpha-Synuclein; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
LRRK2; Parkinson’s disease; transgenic mice; α-synuclein