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LRRK2 deficiency impacts ceramide metabolism in brain

Ferrazza, R; Cogo, S; Melrose, H; Bubacco, L; Greggio, E; Guella, G; Civiero, L; (2016) LRRK2 deficiency impacts ceramide metabolism in brain. Biochemical and Biophysical Research Communications , 478 (3) pp. 1141-1146. 10.1016/j.bbrc.2016.08.082. Green open access

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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.

Type: Article
Title: LRRK2 deficiency impacts ceramide metabolism in brain
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bbrc.2016.08.082
Publisher version: http://doi.org/10.1016/j.bbrc.2016.08.082
Language: English
Additional information: © 2016 Elsevier Inc. All rights reserved. This manuscript version is made available under a Creative Commons Attribution Non-commercial Non-derivative 4.0 International license (CC BY-NC-ND 4.0). This license allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licenses are available at https://creativecommons.org/licenses/. Access may be initially restricted by the publisher.
Keywords: Gaucher's disease, Glucocerebrosidase, Lipidomics, Mass spectrometry, Parkinson's disease, Sphingolipids
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: http://discovery.ucl.ac.uk/id/eprint/1508867
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