@article{0ace25e3de5b43708d20b13d6bc1b114,
title = "Overexpression of Parkinson{\textquoteright}s disease-associated mutation LRRK2 G2019S in mouse forebrain induces behavioral deficits and α-synuclein pathology",
abstract = "Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as an unambiguous cause of late-onset, autosomal-dominant familial Parkinson{\textquoteright}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 CAMKIIα promoter (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.",
keywords = "LRRK2, Parkinson{\textquoteright}s disease, Transgenic mice, α-synuclein",
author = "Yulan Xiong and Stewart Neifert and Karuppagounder, {Senthilkumar S.} and Stankowski, {Jeannette N.} and Lee, {Byoung Dae} and Grima, {Jonathan C.} and Guanxing Chen and Ko, {Han Seok} and Yunjong Lee and Debbie Swing and Lino Tessarollo and Dawson, {Ted M.} and Dawson, {Valina L.}",
note = "Funding Information: This work was supported from National Institutes of Health (NIH)/National Institute on Aging Grant K01-AG046366 (Y.X.), the William N. & Bernice E. Bumpus Foundation Innovation Awards (Y.X.), start-up fund and SUCCESS-FYI Intramural Grant from Kansas State University College of Veterinary Medicine (Y.X.), National Science Foundation Graduate Research Fellowship Award (J.C.G.), the Thomas Shortman Training Fund Graduate Scholarship Award (J.C.G.), the Axol Science Scholarship Award (J.C.G.), NIH/National Institute of Neurological Disorders and Stroke (NINDS) Grant NS-082205 (H.S.K.), NIH/NINDS Grant NS-38377 (H.S.K., T.M.D., and V.L.D.), and the JPB Foundation (T.M.D.). T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. The authors acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation and the Diana Helis Henry Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital, the Johns Hopkins University School of Medicine, and the Foundation{\textquoteright}s Parkinson{\textquoteright}s Disease Programs. Funding Information: This work was supported from National Institutes of Health (NIH)/National Institute on Aging Grant K01-AG046366 (Y.X.), the William N. & Bernice E. Bumpus Foundation Innovation Awards (Y.X.), start-up fund and SUCCESSFYI Intramural Grant from Kansas State University College of Veterinary Medicine (Y.X.), National Science Foundation Graduate Research Fellowship Award (J.C.G.), the Thomas Shortman Training Fund Graduate Scholarship Award (J.C.G.), the Axol Science Scholarship Award (J.C.G.), NIH/National Institute of Neurological Disorders and Stroke (NINDS) Grant NS-082205 (H.S.K.), NIH/NINDS Grant NS-38377 (H.S.K., T.M.D., and V.L.D.), and the JPB Foundation (T.M.D.). T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. The authors acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation and the Diana Helis Henry Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital, the Johns Hopkins University School of Medicine, and the Foundation?s Parkinson?s Disease Programs Publisher Copyright: {\textcopyright} 2017 Xiong et al.",
year = "2017",
doi = "10.1523/ENEURO.0004-17.2017",
language = "English (US)",
volume = "4",
journal = "eNeuro",
issn = "2373-2822",
publisher = "Society for Neuroscience",
number = "2",
}