Formation of Templated Inclusions in a Forebrain α-synuclein Mouse Model is Independent of LRRK2

Overview

Journal Neurobiol Dis

Specialty Neurology

Date 2024 Mar 4

PMID 38435455

Authors

Dylan J Dues

Yue Ma

An Phu Tran Nguyen

Alina V Offerman

Ian Beddows

Darren J Moore

Affiliations

Soon will be listed here.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein share enigmatic roles in the pathobiology of Parkinson's disease (PD). 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 genotype on the formation of α-synuclein inclusions was evaluated at 1-month post-injection. Neither deletion of 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 . There was, however, a modest reduction in microglial activation induced by PFF delivery in the hippocampus of 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.

Citing Articles

LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression.

Lubben N, Brynildsen J, Webb C, Li H, Leyns C, Changolkar L Transl Neurodegener. 2024; 13(1):13.

PMID: 38438877 PMC: 10910783. DOI: 10.1186/s40035-024-00403-2.

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