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

Dylan J Dues; Yue Ma; An Phu Tran Nguyen; Alina V Offerman; Ian Beddows; Darren J Moore

doi:10.1016/j.nbd.2023.106338

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

Neurobiol Dis. 2023 Oct 28:106338. doi: 10.1016/j.nbd.2023.106338. Online ahead of print.

Authors

Dylan J Dues¹, Yue Ma¹, An Phu Tran Nguyen¹, Alina V Offerman¹, Ian Beddows², Darren J Moore³

Affiliations

¹ Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.
² Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
³ Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA. Electronic address: darren.moore@vai.org.

PMID: 39492414
DOI: 10.1016/j.nbd.2023.106338

Abstract

Leucine-rich repeat kinase 2 (LRRK2) and α-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 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 of LRRK2 genotype on the formation of α-synuclein inclusions was evaluated at 1-month post-injection. Neither deletion of LRRK2 nor 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 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 α-synuclein-induced neuroinflammation. Collectively, our data indicate that the pathological accumulation of α-synuclein in the mouse forebrain is largely independent of LRRK2.

Keywords: Alpha-synuclein; Animal models; LRRK2; Lewy body; Microglia; Neurodegeneration; Parkinson's disease; Protein aggregation.