Neuron-autonomous susceptibility to induced synuclein aggregation is exacerbated by endogenous Lrrk2 mutations and ameliorated by Lrrk2 genetic knock-out.

ABSTRACT: Neuronal aggregates containing ?-synuclein are a pathological hallmark of several degenerative diseases; including Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies. Understanding the process of ?-synuclein aggregation, and discovering means of preventing it, may help guide therapeutic strategy and drug design. Recent advances provide tools to induce ?-synuclein aggregation in neuronal cultures. Application of exogenous pre-formed fibrillar ?-synuclein induces pathological phosphorylation and accumulation of endogenous ?-synuclein, typical of that seen in disease. Genomic variability and mutations in ?-synuclein and leucine-rich repeat kinase 2 proteins are the major genetic risk factors for Parkinson's disease. Reports demonstrate fibril-induced ?-synuclein aggregation is increased in cells from leucine-rich repeat kinase 2 pathogenic mutant (G2019S) overexpressing mice, and variously decreased by leucine-rich repeat kinase 2 inhibitors. Elsewhere in vivo antisense knock-down of leucine-rich repeat kinase 2 protein has been shown to protect mice from fibril-induced ?-synuclein aggregation, whereas kinase inhibition did not. To help bring clarity to this issue, we took a purely genetic approach in a standardized neuron-enriched culture, lacking glia. We compared fibril treatment of leucine-rich repeat kinase 2 germ-line knock-out, and G2019S germ-line knock-in, mouse cortical neuron cultures with those from littermates. We found leucine-rich repeat kinase 2 knock-out neurons are resistant to ?-synuclein aggregation, which predominantly forms within axons, and may cause axonal fragmentation. Conversely, leucine-rich repeat kinase 2 knock-in neurons are more vulnerable to fibril-induced ?-synuclein accumulation. Protection and resistance correlated with basal increases in a lysosome marker in knock-out, and an autophagy marker in knock-in cultures. The data add to a growing number of studies that argue leucine-rich repeat kinase 2 silencing, and potentially kinase inhibition, may be a useful therapeutic strategy against synucleinopathy.

SUBMITTER: MacIsaac S 

PROVIDER: S-EPMC7273240 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature