In vivo susceptibility to energy failure parkinsonism and LRRK2 kinase activity

• DOI: 10.1016/j.nbd.2021.105579
• Publication Date: 2021-12-03T17:56:21Z
• Authors: Salvatore Novello; Daniela Mercatelli; Federica Albanese; Chiara Domenicale; Alberto Brugnoli; Elisabetta D'Aversa; Silvia Vantaggiato; Sandra Dovero; Valentina Murtaj; Luca Presotto; Monica Borgatti; Derya R. Shimshek; Erwan Bezard; Rosa Maria Moresco; Sara Belloli; Michele Morari
• Keywords: MPTP; LRRK2; Neurotoxin

The G2019S mutation of LRRK2 represents a risk factor for idiopathic Parkinson's disease. Here, we investigate whether kinase activity regulates susceptibility to the environmental toxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). knock-in mice (bearing enhanced activity) showed greater nigro-striatal degeneration compared knock-out, kinase-dead and wild-type following subacute MPTP treatment. inhibitors PF-06447475 MLi-2, tested under preventive or therapeutic treatments, protected against nigral dopamine cell loss in mice. MLi-2 also rescued striatal dopaminergic terminal both Immunoblot analysis Serine935 phosphorylation levels confirmed target engagement inhibitors. However, abolished phosphoSerine935 striatum midbrain whereas partly reduced genotypes. In vivo ex uptake 18-kDa translocator protein (TSPO) ligand [18F]-VC701 revealed similar TSPO binding MPTP-treated which was consistent with an increased GFAP expression as by Real Time PCR. We conclude that G2019S, likely through activity, confers mitochondrial toxin-induced parkinsonism. are neuroprotective this model.