Formation of templated inclusions in a forebrain -synuclein mouse model is independent of LRRK2

Leucine-rich repeat kinase 2 (LRRK2) and alpha-synuclein share enigmatic roles in the pathobiology of Parkinson's disease (PD). LRRK2 mutations are a common genetic cause of PD which, in addition to neurodegeneration, often present with abnormal deposits of alpha-synuclein in the form of Lewy-related pathology. As Lewy-related pathology is a prominent neuropathologic finding in sporadic PD, the relationship between LRRK2 and alpha-synuclein has garnered considerable interest. However, whether and how LRRK2 might influence the accumulation of Lewyrelated pathology remains poorly understood. Through stereotactic injection of mouse alpha-synuclein pre-formed fibrils (PFF), we modeled the spread of Lewy-related pathology within forebrain regions where LRRK2 is most highly expressed. The impact of LRRK2 genotype on the formation of alpha-synuclein inclusions was evaluated at 1month post-injection. Neither deletion of LRRK2 nor G2019S LRRK2 knockin appreciably altered the burden of alpha-synuclein pathology at this early timepoint. These observations fail to provide support for a robust pathophysiologic interaction between LRRK2 and alpha-synuclein in the forebrain in vivo. There was, however, a modest reduction in microglial activation induced by PFF delivery in the hippocampus of LRRK2 knockout mice, suggesting that LRRK2 may contribute to alpha-synuclein-induced neuroinflammation. Collectively, our data indicate that the pathological accumulation of alpha-synuclein in the mouse forebrain is largely independent of LRRK2.