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000164913 1001_ $$00000-0002-6311-5273$$aKedariti, Maria$$b0
000164913 245__ $$aLRRK2 kinase activity regulates GCase level and enzymatic activity differently depending on cell type in Parkinson's disease.
000164913 260__ $$aLondon [u.a.]$$bNature Publ. Group$$c2022
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000164913 520__ $$aLeucine-rich repeat kinase 2 (LRRK2) is a kinase involved in different cellular functions, including autophagy, endolysosomal pathways, and immune function. Mutations in LRRK2 cause autosomal-dominant forms of Parkinson's disease (PD). Heterozygous mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), are the most common genetic risk factors for PD. Moreover, GCase function is altered in idiopathic PD and in other genetic forms of the disease. Recent work suggests that LRRK2 kinase activity can regulate GCase function. However, both a positive and a negative correlation have been described. To gain insights into the impact of LRRK2 on GCase, we performed a comprehensive analysis of GCase levels and activity in complementary LRRK2 models, including (i) LRRK2 G2019S knock in (GSKI) mice, (ii) peripheral blood mononuclear cell (PBMCs), plasma, and fibroblasts from PD patients carrying LRRK2 G2019S mutation, (iii) patient iPSCs-derived neurons; (iv) endogenous and overexpressed cell models. In some of these models we found a positive correlation between the activities of LRRK2 and GCase, which was further confirmed in cell lines with genetic and pharmacological manipulation of LRRK2 kinase activity. GCase protein level is reduced in GSKI brain tissues and in G2019S iPSCs-derived neurons, but increased in fibroblasts and PBMCs from patients, suggesting cell-type-specific effects. Overall, our study indicates that LRRK2 kinase activity affects both the levels and the catalytic activity of GCase in a cell-type-specific manner, with important implications in the context of therapeutic application of LRRK2 inhibitors in GBA1-linked and idiopathic PD.
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000164913 7001_ $$aFrattini, Emanuele$$b1
000164913 7001_ $$0P:(DE-2719)2811884$$aBaden, Pascale$$b2$$udzne
000164913 7001_ $$aCogo, Susanna$$b3
000164913 7001_ $$00000-0002-5334-155X$$aCiviero, Laura$$b4
000164913 7001_ $$aZiviani, Elena$$b5
000164913 7001_ $$aZilio, Gianluca$$b6
000164913 7001_ $$0P:(DE-2719)9001762$$aBertoli, Federico$$b7$$udzne
000164913 7001_ $$aAureli, Massimo$$b8
000164913 7001_ $$aKaganovich, Alice$$b9
000164913 7001_ $$00000-0002-1058-3831$$aCookson, Mark R$$b10
000164913 7001_ $$00000-0003-3569-8990$$aStefanis, Leonidas$$b11
000164913 7001_ $$00000-0002-4933-2618$$aSurface, Matthew$$b12
000164913 7001_ $$0P:(DE-2719)2810385$$aDeleidi, Michela$$b13$$udzne
000164913 7001_ $$00000-0001-6478-026X$$aDi Fonzo, Alessio$$b14
000164913 7001_ $$aAlcalay, Roy N$$b15
000164913 7001_ $$aRideout, Hardy$$b16
000164913 7001_ $$00000-0002-8172-3598$$aGreggio, Elisa$$b17
000164913 7001_ $$00000-0001-7421-8705$$aPlotegher, Nicoletta$$b18
000164913 773__ $$0PERI:(DE-600)2819218-7$$a10.1038/s41531-022-00354-3$$gVol. 8, no. 1, p. 92$$p92$$tnpj Parkinson's Disease$$v8$$x2373-8057$$y2022
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