Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

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Abstract

Ceramide is a bioactive sphingolipid involved in numerous cellular processes. In addition to being the precursor of complex sphingolipids, ceramides can act as second messengers, especially when they are generated at the plasma membrane of cells. Its metabolic dysfunction may lead to or be a consequence of an underlying disease. Recent reports on transcriptomics and electrospray ionization mass spectrometry analysis have demonstrated the variation of specific levels of sphingolipids and enzymes involved in their metabolism in different neurodegenerative diseases. In the present review, we highlight the most relevant discoveries related to ceramide and neurodegeneration, with a special focus on Parkinson’s disease.

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Epidemiology of Parkinson's disease.

Ole-Bjørn Tysnes, Anette Storstein (2017)

Parkinson's disease (PD) affects 1-2 per 1000 of the population at any time. PD prevalence is increasing with age and PD affects 1% of the population above 60 years. The main neuropathological finding is α-synuclein-containing Lewy bodies and loss of dopaminergic neurons in the substantia nigra, manifesting as reduced facilitation of voluntary movements. With progression of PD, Lewy body pathology spreads to neocortical and cortical regions. PD is regarded as a movement disorder with three cardinal signs: tremor, rigidity and bradykinesia. A recent revision of the diagnostic criteria excludes postural instability as a fourth hallmark and defines supportive criteria, absolute exclusion criteria and red flags. Non-motor symptoms in PD have gained increasing attention and both motor and non-motor signs are now included among the supportive criteria. The cause of PD is unknown in most cases. Genetic risk factors have been identified, including monogenetic causes that are rare in unselected populations. Some genetic factor can be identified in 5-10% of the patients. Several environmental factors are associated with increased risk of PD. Autopsy studies show that the clinical diagnosis of PD is not confirmed at autopsy in a significant proportion of patients. Revised diagnostic criteria are expected to improve the clinician´s accuracy in diagnosing PD. Increasing knowledge on genetic and environmental risk factors of PD will probably elucidate the cause of this disease within the near future.

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Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease

Mike A Nalls, Nathan Pankratz, Christina Lill … (2014)

We conducted a meta analysis of Parkinson’s disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as genome-wide significant; these and six additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 novel loci. Conditional analyses within loci show four loci including GBA, GAK/DGKQ, SNCA, and HLA contain a secondary independent risk variant. In total we identified and replicated 28 independent risk variants for Parkinson disease across 24 loci. While the effect of each individual locus is small, a risk profile analysis revealed a substantial cummulative risk in a comparison highest versus lowest quintiles of genetic risk (OR=3.31, 95% CI: 2.55, 4.30; p-value = 2×10−16). We also show 6 risk loci associated with proximal gene expression or DNA methylation.

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Principles of bioactive lipid signalling: lessons from sphingolipids.

Yusuf Hannun, Lina M. Obeid (2008)

It has become increasingly difficult to find an area of cell biology in which lipids do not have important, if not key, roles as signalling and regulatory molecules. The rapidly expanding field of bioactive lipids is exemplified by many sphingolipids, such as ceramide, sphingosine, sphingosine-1-phosphate (S1P), ceramide-1-phosphate and lyso-sphingomyelin, which have roles in the regulation of cell growth, death, senescence, adhesion, migration, inflammation, angiogenesis and intracellular trafficking. Deciphering the mechanisms of these varied cell functions necessitates an understanding of the complex pathways of sphingolipid metabolism and the mechanisms that regulate lipid generation and lipid action.

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Author and article information

Contributors

Elisabetta Albi: Role: Academic Editor

Alice V. Alessenko: Role: Academic Editor

Journal

Journal ID (nlm-ta): Biomolecules

Journal ID (iso-abbrev): Biomolecules

Journal ID (publisher-id): biomolecules

Title: Biomolecules

Publisher: MDPI

ISSN (Electronic): 2218-273X

Publication date (Electronic): 25 June 2021

Publication date Collection: July 2021

Volume: 11

Issue: 7

Electronic Location Identifier: 945

Affiliations

[1 ]Clinical Neurosciences Research Laboratories, Health Research Institute of Santiago de Compostela (IDIS), Travesa da Choupana s/n, 15706 Santiago de Compostela, Spain; antia.custodia.malvido@ 123456sergas.es (A.C.); marta.aramburu.nunez@ 123456sergas.es (M.A.-N.); clara.correa.paz@ 123456sergas.es (C.C.-P.); adrian.posado.fernandez@ 123456sergas.es (A.P.-F.); jose.castillo.sanchez@ 123456sergas.es (J.C.)

[2 ]Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country, P.O. Box 644, 48980 Bilbao, Spain; ana.gomezlarrauri@ 123456osakidetza.eus (A.G.-L.); antonio.gomez@ 123456ehu.eus (A.G.-M.)

[3 ]Respiratory Department, Cruces University Hospital, Barakaldo, 48903 Bizkaia, Spain

Author notes

[* ]Correspondence: tomas.sobrino.moreiras@ 123456sergas.es (T.S.); alberto.ouro.villasante@ 123456sergas.es (A.O.); Tel.: +34-981951098 (T.S.); +34-664326589 (A.O.)

[†]

These authors contributed equally to this work.

Author information

Marta Aramburu-Núñez https://orcid.org/0000-0002-1212-9851

Tomás Sobrino https://orcid.org/0000-0002-9760-8690

Alberto Ouro https://orcid.org/0000-0003-4359-1704

Article

Publisher ID: biomolecules-11-00945

DOI: 10.3390/biom11070945

PMC ID: 8301871

PubMed ID: 34202192

SO-VID: 8a5929fe-ac8f-4950-b353-38f2a8911af8

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

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Abstract

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Cancer Metabolism

Most cited references 218

Epidemiology of Parkinson's disease.

Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease

Principles of bioactive lipid signalling: lessons from sphingolipids.

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