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@ARTICLE{Kedariti:164913,
      author       = {Kedariti, Maria and Frattini, Emanuele and Baden, Pascale
                      and Cogo, Susanna and Civiero, Laura and Ziviani, Elena and
                      Zilio, Gianluca and Bertoli, Federico and Aureli, Massimo
                      and Kaganovich, Alice and Cookson, Mark R and Stefanis,
                      Leonidas and Surface, Matthew and Deleidi, Michela and Di
                      Fonzo, Alessio and Alcalay, Roy N and Rideout, Hardy and
                      Greggio, Elisa and Plotegher, Nicoletta},
      title        = {{LRRK}2 kinase activity regulates {GC}ase level and
                      enzymatic activity differently depending on cell type in
                      {P}arkinson's disease.},
      journal      = {npj Parkinson's Disease},
      volume       = {8},
      issn         = {2373-8057},
      address      = {London [u.a.]},
      publisher    = {Nature Publ. Group},
      reportid     = {DZNE-2022-01324},
      pages        = {92},
      year         = {2022},
      note         = {CC BY},
      abstract     = {Leucine-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.},
      cin          = {AG Deleidi},
      ddc          = {610},
      cid          = {I:(DE-2719)1210011},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35853899},
      pmc          = {pmc:PMC9296523},
      doi          = {10.1038/s41531-022-00354-3},
      url          = {https://pub.dzne.de/record/164913},
}