Overexpression of Parkinson's Disease-Associated Mutation LRRK2 G2019S in Mouse Forebrain Induces Behavioral Deficits and alpha-Synuclein Pathology

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dc.contributor.author Xiong, Y. L.
dc.contributor.author Neifert, S.
dc.contributor.author Karuppagounder, S. S.
dc.contributor.author Stankowski, J. N.
dc.contributor.author Lee, B. D.
dc.contributor.author Grima, J. C.
dc.contributor.author Chen, G. X.
dc.contributor.author Ko, H. S.
dc.contributor.author Lee, Y.
dc.contributor.author Swing, D.
dc.contributor.author Tessarollo, L.
dc.contributor.author Dawson, T. M.
dc.contributor.author Dawson, V. L.
dc.date.accessioned 2017-11-30T21:38:30Z
dc.date.available 2017-11-30T21:38:30Z
dc.identifier.uri http://hdl.handle.net/2097/38283
dc.description Citation: Xiong, Y. L., Neifert, S., Karuppagounder, S. S., Stankowski, J. N., Lee, B. D., Grima, J. C., . . . Dawson, V. L. (2017). Overexpression of Parkinson's Disease-Associated Mutation LRRK2 G2019S in Mouse Forebrain Induces Behavioral Deficits and alpha-Synuclein Pathology. Eneuro, 4(2), 10. doi:10.1523/eneuro.0004-17.2017
dc.description.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'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 CAMKII alpha promoter (CAMKII alpha-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 alpha-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.
dc.relation.uri https://doi.org/10.1523/eneuro.0004-17.2017
dc.rights Attribution 4.0 International (CC BY 4.0)
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.subject Parkinson'S Disease
dc.subject Lrrk2
dc.subject Transgenic Mice
dc.subject Beta-Synuclein
dc.subject Midbrain Dopaminergic-Neurons
dc.subject R1441C Lrrk2
dc.title Overexpression of Parkinson's Disease-Associated Mutation LRRK2 G2019S in Mouse Forebrain Induces Behavioral Deficits and alpha-Synuclein Pathology
dc.type Article
dc.date.published 2017
dc.citation.doi 10.1523/eneuro.0004-17.2017
dc.citation.issn 2373-2822
dc.citation.issue 2
dc.citation.jtitle Eneuro
dc.citation.spage 10
dc.citation.volume 4
dc.contributor.authoreid yulanx
dc.contributor.kstate Xiong, Yulan


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