In vivo susceptibility to energy failure parkinsonism and LRRK2 kinase activity
| Autor: | 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 |
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| Přispěvatelé: | Novello, S, Mercatelli, D, Albanese, F, Domenicale, C, Brugnoli, A, D'Aversa, E, Vantaggiato, S, Dovero, S, Murtaj, V, Presotto, L, Borgatti, M, Shimshek, D, Bezard, E, Moresco, R, Belloli, S, Morari, M |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Parkinson's disease
LS5_11 Neurosciences. Biological psychiatry. Neuropsychiatry PF-06447475 LRRK2 knock-out Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 NO Mice Parkinsonian Disorders Animals pSer935 LRRK2 Phosphorylation G2019S LRRK2 LRRK2 kinase-dead MLi-2 MPTP TSPO [(18)F]-VC701 Parkinson Disease [18F]-VC701 Corpus Striatum nervous system diseases F]-VC701 Neurology nervous system Mutation [ RC321-571 |
| Zdroj: | Neurobiology of Disease, Vol 162, Iss, Pp 105579-(2022) Neurobiology of disease (Online) 162 (2022): 105579. doi:10.1016/j.nbd.2021.105579 info:cnr-pdr/source/autori:Novello S.; Mercatelli D.; Albanese F.; Domenicale C.; Brugnoli A.; D'Aversa E.; Vantaggiato S.; Dovero S.; Murtaj V.; Presotto L.; Borgatti M.; Shimshek D.R.; Bezard E.; Moresco R.M.; Belloli S.; Morari M./titolo:In vivo susceptibility to energy failure parkinsonism and LRRK2 kinase activity/doi:10.1016%2Fj.nbd.2021.105579/rivista:Neurobiology of disease (Online)/anno:2022/pagina_da:105579/pagina_a:/intervallo_pagine:105579/volume:162 |
| DOI: | 10.1016/j.nbd.2021.105579 |
| Popis: | The G2019S mutation of LRRK2 represents a risk factor for idiopathic Parkinson's disease. Here, we investigate whether LRRK2 kinase activity regulates susceptibility to the environmental toxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). 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. MLi-2 also rescued striatal dopaminergic terminal degeneration in both G2019S knock-in and wild-type mice. Immunoblot analysis of LRRK2 Serine935 phosphorylation levels confirmed target engagement of LRRK2 inhibitors. However, MLi-2 abolished phosphoSerine935 levels in the striatum and midbrain of both wild-type and G2019S knock-in mice whereas PF-06447475 partly reduced phosphoSerine935 levels in the midbrain of both genotypes. In vivo and ex vivo uptake of the 18-kDa translocator protein (TSPO) ligand [18F]-VC701 revealed a similar TSPO binding in MPTP-treated wild-type and G2019S knock-in mice which was consistent with an increased GFAP striatal expression as revealed by Real Time PCR. We conclude that LRRK2 G2019S, likely through enhanced kinase activity, confers greater susceptibility to mitochondrial toxin-induced parkinsonism. LRRK2 kinase inhibitors are neuroprotective in this model. |
| Databáze: | OpenAIRE |
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