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bioRxiv · 10.1101/2023.08.19.553965

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

Dues, D. J.·Ma, Y.·Nguyen, A. P. T.·Offerman, A. V.·Beddows, I.·Moore, D. J.
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Abstract

Leucine-rich repeat kinase 2 (LRRK2) and -synuclein share enigmatic roles in the pathobiology of Parkinsons disease (PD). LRRK2 mutations are a common genetic cause of PD which, in addition to neurodegeneration, often present with abnormal deposits of -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 -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 -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 -synuclein inclusions was evaluated at 1-month post-injection. Neither deletion of LRRK2 nor G2019S LRRK2 knockin appreciably altered the burden of - synuclein pathology at this early timepoint. These observations fail to provide support for a robust pathophysiologic interaction between LRRK2 and -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 -synuclein-induced neuroinflammation. Collectively, our data indicate that the pathological accumulation of -synuclein in the mouse forebrain is largely independent of LRRK2. HighlightsO_LIAdult mice accumulate -synuclein pathology in the hippocampus and cortex following stereotactic injection with -synuclein PFFs, with negligible influence of LRRK2 genotype. C_LIO_LIHippocampal and cortical -synuclein pathology elicits the concomitant accrual of phosphorylated tau, reactive astrogliosis, and microglial activation. C_LIO_LIAbsence of endogenous LRRK2 attenuates microglial activation in the dorsal hippocampus induced by PFFs, but not in the entorhinal cortex. C_LIO_LIAccumulation of -synuclein inclusions and related neuropathologic changes were strongly associated across the hippocampal dorsal-ventral axis, regardless of LRRK2 genotype. C_LI

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Dues, D. J., Ma, Y., Nguyen, A. P. T., Offerman, A. V., Beddows, I., Moore, D. J.. 2023-08-20. Formation of templated inclusions in a forebrain α-synuclein mouse model is independent of LRRK2. https://doi.org/10.1101/2023.08.19.553965

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