Emerging pathways in genetic Parkinson's disease: Potential role of ceramide metabolism in Lewy body disease

Brás, José; Singleton, Andrew B.; Cookson, Mark; Hardy, John

doi:10.1111/j.1742-4658.2008.06709.x

Cited by 119 publications

(105 citation statements)

References 58 publications

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“…Moreover, more needs to be done to understand if LRRK2 directly or indirectly regulates Cer metabolism through other pathways. Our results together with other recently published papers [2,5,7,11,27,33] suggest that PD shares several features with sphingolipid disorders, opening new avenues for the identification of novel therapeutic strategies.…”

Section: Discussionmentioning

confidence: 64%

“…Several studies have provided evidence that sphingolipid levels are often altered in neurodegenerative diseases [2][3][4]. Ceramides (Cer), components of all major sphingolipid species in the brain, were found to have a defective homeostasis in neurodegenerative disorders with LBs pathology, including PD [2,[5][6][7]. This class of lipids is generated by three pathways: i) the sphingomyelin hydrolysis that occurs at the plasma membrane, ii) the de novo synthesis taking place within endoplasmic reticulum (ER)/Golgi apparatus and iii) the salvage pathway in the endo-lysosomal compartment.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LRRK2 deficiency impacts ceramide metabolism in brain

Ferrazza

Cogo

Melrose

et al. 2016

Biochemical and Biophysical Research Communications

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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.

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

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LRRK2 deficiency impacts ceramide metabolism in brain

Ferrazza

Cogo

Melrose

et al. 2016

Biochemical and Biophysical Research Communications

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“…Its pathophysiology involves, e.g., accumulation and spreading of misfolded proteins [48], neuro-inflammation including persistent microglial activity [49], neuro-inflammation including persistent microglial activity [49] and dysfunctions of mitochondrial biogenesis and quality control systems [50]. The latter processes are essentially regulated by bioactive lipids including ceramides, sphingolipids, lysophospholipids, eicosanoids, endocannabinoids, HETEs, omega-3 and omega-6 lipids and EETs [17,[51][52][53][54][55][56][57][58][59]. The relevance of subtle changes in complex regulatory circuits has been taken into account by modern omics-based analysis tools using "gene set enrichment analyses" for the detection of pattern changes [60,61].…”

Section: Discussionmentioning

confidence: 99%

Identification of disease-distinct complex biomarker patterns by means of unsupervised machine-learning using an interactive R toolbox (Umatrix)

et al. 2018

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Background: Unsupervised machine-learned analysis of cluster structures, applied using the emergent self-organizing feature maps (ESOM) combined with the unified distance matrix (U-matrix) has been shown to provide an unbiased method to identify true clusters. It outperforms classical hierarchical clustering algorithms that carry a considerable tendency to produce erroneous results. To facilitate the application of the ESOM/U-matrix method in biomedical research, we introduce the interactive R-based bioinformatics tool "Umatrix", which enables valid identification of a biologically meaningful cluster structure in the data by training a Kohonen-type self-organizing map followed by interface-guided interactive clustering on the emergent U-matrix map. Results: The ability to detect clinical relevant subgroups was applied to a data set comprising plasma concentrations of d = 25 lipid markers including endocannabinoids, lysophosphatidic acids, ceramides and sphingolipids acquired from n = 100 patients with Parkinson's disease and n = 100 controls. Following ESOM training, clear data structures in the high-dimensional data space were observed on the U-matrix, allowing separation of patients from controls almost perfectly. When the data structure was destroyed by Monte-Carlo random resampling, the U-matrix became unstructured and patients and controls were mixed. Obtained results are biologically plausible and supported by empirical evidence of a regulation of several classes of lipids in Parkinson's disease. Conclusions: Sophisticated analysis of structures in biomedical data provides a basis for the mechanistic interpretation of the observations and facilitates subsequent analyses focusing on hypothesis testing. The freely available R library "Umatrix" provides an interactive tool for broader application of unsupervised machine learning on complex biomedical data.

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“…Ceramide is a GCase product, and a genetic-association study has suggested that several genes related to ceramide metabolism are associated with LB pathology (Bras et al , 2008 ). Furthermore, inclusion of α -synuclein in Caenorhabditis elegans increases by 35 % due to deletion of the Lagr-1 gene, a ceramide synthase homologue (van Ham et al , 2008 ).…”

Section: Lipid Alterations and Accumulationmentioning

confidence: 99%

Glucocerebrosidase, a new player changing the old rules in Lewy body diseases

Yang

Lee

Lee³

et al. 2013

Biological Chemistry

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Mutations in the gene encoding glucocerebrosidase ( GBA1 ) cause Gaucher disease (GD), a lysosomal storage disease with recessive inheritance. Glucocerebrosidase (GCase) is a lysosomal lipid hydrolase that digests glycolipid substrates, such as glucosylceramide and glucosylsphingosine. GBA1 mutations have been implicated in Lewy body diseases (LBDs), such as Parkinson ' s disease and dementia with Lewy bodies. Parkinsonism occurs more frequently in certain types of GD, and GBA1 mutation carriers are more likely to have LBDs than noncarriers. Furthermore, GCase is often found in Lewy bodies, which are composed of α -synuclein fibrils as well as a variety of proteins and vesicles. In this review, we discuss potential mechanisms of action of GBA1 mutations in LBDs with particular emphasis on α -synuclein aggregation by reviewing the current literature on the role of GCase in lysosomal functions and glycolipid metabolism.

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Emerging pathways in genetic Parkinson's disease: Potential role of ceramide metabolism in Lewy body disease

Cited by 119 publications

References 58 publications

LRRK2 deficiency impacts ceramide metabolism in brain

LRRK2 deficiency impacts ceramide metabolism in brain

Identification of disease-distinct complex biomarker patterns by means of unsupervised machine-learning using an interactive R toolbox (Umatrix)

Glucocerebrosidase, a new player changing the old rules in Lewy body diseases

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