PT - JOURNAL ARTICLE AU - Yulan Xiong AU - Stewart Neifert AU - Senthilkumar S. Karuppagounder AU - Jeannette N. Stankowski AU - Byoung Dae Lee AU - Jonathan C. Grima AU - Guanxing Chen AU - Han Seok Ko AU - Yunjong Lee AU - Debbie Swing AU - Lino Tessarollo AU - Ted M. Dawson AU - Valina L. Dawson TI - Overexpression of Parkinson’s Disease-Associated Mutation LRRK2 G2019S in Mouse Forebrain Induces Behavioral Deficits and α-Synuclein Pathology AID - 10.1523/ENEURO.0004-17.2017 DP - 2017 Mar 06 TA - eneuro PG - ENEURO.0004-17.2017 4099 - http://www.eneuro.org/content/early/2017/03/06/ENEURO.0004-17.2017.short 4100 - http://www.eneuro.org/content/early/2017/03/06/ENEURO.0004-17.2017.full AB - 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 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.Significance Statement Mutations in LRRK2 are the most common genetic cause for both familial and sporadic Parkinson’s disease (PD) to date with the G2019S LRRK2 (LRRK2 GS) being the most prevalent mutation. The clinical presentation of patients carrying LRRK2 GS is indistinguishable from sporadic disease in many cases. Many lines of evidence indicate that LRRK2 GS has increased kinase activity and in vitro LRRK2 inhibitors or kinase-dead G2019S/D1994A double mutants (LRRK2 GS/DA) reduce LRRK2 GS-mediated toxicity, indicating that LRRK2 associated toxicity is kinase-dependent. However, this concept remains controversial. To address this question in vivo, we developed a new tet-inducible conditional transgenic LRRK2 GS and LRRK2 GS/DA mouse model, which exhibits behavioral deficits and α-synuclein pathology in a kinase dependent manner.