LRRK2 deficiency impacts ceramide metabolism in brain

Ruggero Ferrazza, Susanna Cogo, Heather Melrose, Luigi Bubacco, Elisa Greggio, Graziano Guella, Laura Civiero, Nicoletta Plotegher

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1141-1146
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume478
Issue number3
DOIs
StatePublished - Sep 23 2016

Keywords

  • Gaucher's disease
  • Glucocerebrosidase
  • Lipidomics
  • Mass spectrometry
  • Parkinson's disease
  • Sphingolipids

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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