title: LRRK2 deficiency impacts ceramide metabolism in brain.
abstract: Mutations in LRRK2 gene cause inherited Parkinson's disease (PD) and variations around LRRK2 act as risk factor for disease. Similar to sporadic disease, LRRK2-linked cases show late onset and, typically, the presence of proteinaceous inclusions named Lewy bodies (LBs) in neurons. Recently, defects on ceramide (Cer) metabolism have been recognized in PD. In particular, heterozygous mutations in the gene encoding for glucocerebrosidase (GBA1), a lysosomal enzyme converting glucosyl-ceramides (Glc-Cer) into Cer, increase the risk of developing PD. Although several studies have linked LRRK2 with membrane-related processes and autophagic-lysosomal pathway regulation, whether this protein impinges on the Cer pathway has not been addressed. Here, using a targeted lipidomics approach, we report an altered sphingolipid composition in Lrrk2(-/-) mouse brains. In particular, we observe a significant increase of Cer levels in Lrrk2(-/-) mice and direct effects on GBA1. Collectively, our results suggest a link between LRRK2 and Cer metabolism, providing new insights into the possible role of this protein in sphingolipids metabolism, with implications for PD therapeutics.
authors.affiliation: Bioorganic Chemistry Laboratory, Department of Physics, University of Trento, Via Sommarive 14, 38123, Povo, Trento, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: Ferrazza
authors.affiliation: Department of Biology, University of Padova, Via U. Bassi 58/b, 35131, Padova, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Cogo
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, 32224, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Melrose
authors.affiliation: Department of Biology, University of Padova, Via U. Bassi 58/b, 35131, Padova, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Bubacco
authors.affiliation: Department of Biology, University of Padova, Via U. Bassi 58/b, 35131, Padova, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Greggio
authors.affiliation: Bioorganic Chemistry Laboratory, Department of Physics, University of Trento, Via Sommarive 14, 38123, Povo, Trento, Italy; Biophysical Institute, CNR, Via alla Cascata 56/C, 38123, Povo, Trento, Italy.
authors.forename: Graziano
authors.initials: G
authors.lastname: Guella
authors.affiliation: Department of Biology, University of Padova, Via U. Bassi 58/b, 35131, Padova, Italy. Electronic address: laura.civiero@unipd.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Civiero
authors.affiliation: Department of Biology, University of Padova, Via U. Bassi 58/b, 35131, Padova, Italy. Electronic address: n.plotegher@ucl.ac.uk.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Plotegher
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism*; D015536:Down-Regulation; D005962:Glucosylceramidase / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000172:deficiency* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013107:Sphingolipids / Q000378:metabolism
chemical_list: D002518:Ceramides; D013107:Sphingolipids; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D005962:Glucosylceramidase
keywords: Gaucher's disease; Glucocerebrosidase; Lipidomics; Mass spectrometry; Parkinson's disease; Sphingolipids