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.
Authors report no conflict of interest.
This work was supported by grants from NIH/NIA K01-AG046366 (YX), the William N. & Bernice E. Bumpus Foundation Innovation Awards (YX), start-up fund and SUCCESS-FYI Intramural Grant from Kansas State University College of Veterinary Medicine (YX), National Science Foundation Graduate Research Fellowship Award (JCG), Thomas Shortman Training Fund Graduate Scholarship Award (JCG), Axol Science Scholarship Award (JCG), NIH/NINDS NS082205 (HSK), NIH/NINDS NS38377 (HSK, VLD and TMD), and the JPB Foundation (TMD). TMD 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.