In vivo susceptibility to energy failure parkinsonism and LRRK2 kinase activity

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with a significant proportion of familial (5–6%) and idiopathic (1–2%) Parkinson’s disease (iPD). LRRK2-associated PD is clinically and neuropathologically indistinguishable from iPD, and shows autosomal dominant transmission with incomplete penetrance, suggesting an interplay among G2019S mutation, intrinsic (e.g. age) and environmental (e.g. toxins) factors. The c.6055G > A mutation results in a higher kinase activity which is associated with neurotoxicity. On this basis, LRRK2 kinase inhibitors  are being developed as disease-modifying agents.

The G2019S mutation of LRRK2 represents a risk factor for iPD and in this study, researchers investigated whether LRRK2 kinase activity regulates susceptibility to the environmental toxin MPTP. In addition, the effect of LRRK2 kinase inhibitors was investigated;

Non-invasive and longitudinal preclinical PET-CT imaging of neuroinflammation was performed to assess neurodegeneration in Parkinson disease pathogenesis, by using the 18-kDa translocator protein (TSPO) ligand, [18F]-VC701. The impact of MPTP on neuroinflammation markers was also investigated with PET-CT imaging.

For the imaging study, 8 G2019S KI and 6 WT mice underwent the first CT and PET [18F]VC701 acquisitions before starting MPTP treatment (d0) and the second CT and PET acquisitions at the end of the 7 day-treatment (d7). CT/PET images were processed using Region of Interest (ROI) analysis with brain atlas coregistration and Statistical Parametric Mapping (SPM). SPM is a voxel-based operator-independent analysis that allows the identification of brain regions resulting above a statistical threshold in between groups or conditions comparisons.

G2019S knock-in mice (bearing enhanced kinase activity) showed greater nigro-striatal degeneration compared to LRRK2 knock-out, LRRK2 kinase-dead and wild-type mice following subacute MPTP treatment. LRRK2 kinase inhibitors PF-06447475 and MLi-2, tested under preventive or therapeutic treatments, protected against nigral dopamine cell loss in G2019S knock-in mice. PET imaging with TSPO ligand [18F]-VC701 revealed a similar TSPO binding in MPTP-treated wild-type and G2019S knock-in mice. It was thus concluded that LRRK2 G2019S, likely through enhanced kinase activity, confers greater susceptibility to mitochondrial toxin-induced parkinsonism. LRRK2 kinase inhibitors are neuroprotective in this model.