Evaluating LRRK2 as a therapeutic target in Parkinson's disease Michael X. Henderson1, Chao Peng1, Corey T. McMillan1, Raizel M. Sandler1, Adam Darwich1, Bin Zhang1, Hannah Brown1, John Q. Trojanowski1, Virginia M.-Y. Lee1 1Center for Neurodegenerative Disease Research, University of Pennsylvania
Parkinson's disease (PD) is the most common neurodegenerative movement disorder. The clinical diagnosis of PD is confirmed post-mortem by the presence of intracytoplasmic inclusions termed Lewy bodies, which consist primarily of the synaptic protein α-synuclein. While α-synuclein is thought to be pathogenic in this largely sporadic disease, mutations in several genes can increase the lifetime risk of developing disease. The most commonly mutated gene in PD is leucine-rich repeat kinase (LRRK2). LRRK2 is a broadly-expressed protein with unclear function. It has kinase, GTPase and scaffolding domains and has been implicated in membrane trafficking and cytoskeletal modeling. The most common PD-linked mutation, G2019S, leads to elevated kinase activity, so LRRK2 inhibitors have been the subjects of intense drug development for PD. However, the lack of a reliable preclinical disease model for LRRK2 dysfunction has been a major challenge for the field. We developed cell and animal models to evaluate whether mutant LRRK2*G2019S expression exacerbates the extent or spread of α-synuclein pathology. We then utilized these models to test the efficacy of several top LRRK2 inhibitors to affect α-synuclein pathology. Our data represent important preclinical observations that will inform the development of LRRK2 inhibitors for use in PD patients with and without mutations in LRRK2.