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

Abstract

AbstractLeucine-rich repeat kinase 2 (LRRK2) and α-synuclein share enigmatic roles in the pathobiology of Parkinson’s disease (PD).LRRK2mutations are a common genetic cause of PD which, in addition to neurodegeneration, often present with abnormal deposits of α-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 α-synuclein has garnered considerable interest. However, whether and how LRRK2 might influence the accumulation of Lewy-related pathology remains poorly understood. Through stereotactic injection of mouse α-synuclein pre-formed fibrils (PFF), we modeled the spread of Lewy-related pathology within forebrain regions where LRRK2 is most highly expressed. The impact ofLRRK2genotype on the formation of α-synuclein inclusions was evaluated at 1-month post-injection. Neither deletion ofLRRK2nor G2019S LRRK2 knockin appreciably altered the burden of α- synuclein pathology at this early timepoint. These observations fail to provide support for a robust pathophysiologic interaction between LRRK2 and α-synuclein in the forebrainin vivo. There was, however, a modest reduction in microglial activation induced by PFF delivery in the hippocampus ofLRRK2knockout mice, suggesting that LRRK2 may contribute to α-synuclein-induced neuroinflammation. Collectively, our data indicate that the pathological accumulation of α-synuclein in the mouse forebrain is largely independent of LRRK2.HighlightsAdult mice accumulate α-synuclein pathology in the hippocampus and cortex following stereotactic injection with α-synuclein PFFs, with negligible influence ofLRRK2genotype.Hippocampal and cortical α-synuclein pathology elicits the concomitant accrual of phosphorylated tau, reactive astrogliosis, and microglial activation.Absence of endogenousLRRK2attenuates microglial activation in the dorsal hippocampus induced by PFFs, but not in the entorhinal cortex.Accumulation of α-synuclein inclusions and related neuropathologic changes were strongly associated across the hippocampal dorsal-ventral axis, regardless ofLRRK2genotype.