G2019S-LRRK2 mutation enhances MPTP-linked Parkinsonism in mice

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disease with a heterogeneous etiology that involves genetic and environmental factors or exogenous. Current LRRK2 PD animal models only partly reproduce the characteristics of the disease with very subtle dopaminergic neuron degeneration. We developed a new model of PD that combines a sub-toxic MPTP insult to the G2019S-LRRK2 mutation. Our newly generated mice, overexpressing mutant G2019S-LRRK2 protein in the brain, displayed a mild, age-dependent progressive motor impairment, but no reduction of lifespan. Cortical neurons from G2019S-LRRK2 mice showed an increased vulnerability to stress insults, compared with neurons overexpressing wild-type WT-LRRK2, or non-transgenic (nTg) neurons. The exposure of LRRK2 transgenic mice to a sub-toxic dose of MPTP resulted in severe motor impairment, selective loss of dopamine neurons and increased astrocyte activation, whereas nTg mice with MPTP exposure showed no deficits. Interestingly, mice overexpressing WT-LRRK2 showed a significant impairment that was milder than for the mutant G2019S-LRRK2 mice. L-DOPA treatments could partially improve the movement impairments but did not protect the dopamine neuron loss. In contrast, treatments with an LRRK2 kinase inhibitor significantly reduced the dopaminergic neuron degeneration in this interaction model. Our studies provide a novel LRRK2 gene-MPTP interaction PD mouse model, and a useful tool for future studies of PD pathogenesis and therapeutic intervention.

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

“…The wild-type LRRK2 transgenic mice showed the motor abnormalities even at 12 months of age but significantly differed compared to control mice. Their data showed that the LRRK2 overexpression in mice escalated dopaminergic neurons’ loss when exposed to MPTP doses and suggested that the LRRK2 gene/MPTP interaction mice model could be a useful tool for better understanding in PD investigations [ 152 ]. Guo et al (2016) administered a cumulative dose of 80 mg/kg MPTP (20 mg/kg, four intraperitoneally) in male C57BL/6 mice models.…”

Progress in LRRK2-Associated Parkinson’s Disease Animal Models

“…A recent LRRK2 phosphomimetic (S910A + S935A) KI mouse model has shown a reduction in astrogliosis, while a transgenic OE of LRRK2-G2019S in mice exhibited an increase in astrogliosis (Xiong et al, 2018;Zhou et al, 2018). Another study using G2019S KI mice has exhibited astrogliosis using a sub-toxic dose of MPTP dose to cause DA neurodegeneration (Arbez et al, 2019). Investigation of LRRK2 and astrogliosis using these models may help elucidate potential pathogenic mechanisms for LRRK2 in the CNS.…”

Genetic and Environmental Factors Influence Pleomorphy of lRRK2 Parkinsonism

“…Neurodegeneration associated with LRRK2 G2019S expression is augmented in mice after MPTP administration; however, mice expressing human WT LRRK2 exhibit similar response to MPTP as non-transgenic animals [114,115]. Sub-toxic exposure to MPTP increases motor impairment, dopaminergic cell loss, and astrocyte activation, which can be partially reversed by pharmacological LRRK2 kinase inhibition [115]. On the other hand, mice that lack LRRK2 kinase domain do not show any difference in MPTP sensitivity when compared to WT animals [116].…”

“…1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP), a contaminant of the synthetic opiate meperidine, was identified as a neurotoxic compound leading to an acute form of parkinsonism [112,113]. Neurodegeneration associated with LRRK2 G2019S expression is augmented in mice after MPTP administration; however, mice expressing human WT LRRK2 exhibit similar response to MPTP as non-transgenic animals [114,115]. Sub-toxic exposure to MPTP increases motor impairment, dopaminergic cell loss, and astrocyte activation, which can be partially reversed by pharmacological LRRK2 kinase inhibition [115].…”