The Role of the Ceramide Acyl Chain Length in Neurodegeneration: Involvement of Ceramide Synthases

Ben-David, Oshrit; Futerman, Anthony H.

doi:10.1007/s12017-010-8114-x

Cited by 121 publications

(98 citation statements)

References 56 publications

(76 reference statements)

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“…The relative amounts of different Cer species, as defined by their fatty acyl chain composition, regulate ceramide function in lipid membranes and signaling pathways and was found to be unbalanced in PD brain samples [5,32]. To assess whether the observed increase of total 18:1 Cer in brains was specific to certain acyl chains, we compared their relative amounts across samples, as described in the Methods.…”

Section: Lrrk2 Deficiency Does Not Affect the Cer Fatty Acyl Chain Comentioning

confidence: 99%

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: Lrrk2 Deficiency Does Not Affect the Cer Fatty Acyl Chain Comentioning

confidence: 99%

LRRK2 deficiency impacts ceramide metabolism in brain

Ferrazza

Cogo

Melrose

et al. 2016

Biochemical and Biophysical Research Communications

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“…For instance, ceramide with a C 18 fatty acyl chain (C 18 ceramide) has been suggested to cause apoptosis in certain cancer cells, whereas ceramide with a C 16 fatty acyl chain (C 16 ceramide) has been considered prosurvival (10)(11)(12). The ceramide profile changes in aging and neurodegenerative brains, but whether these alterations contribute to the pathogenesis, and the biological significance of ceramide diversity, are unknown (13).…”

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confidence: 99%

Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

Spassieva

Liu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Sphingolipids exhibit extreme functional and chemical diversity that is in part determined by their hydrophobic moiety, ceramide. In mammals, the fatty acyl chain length variation of ceramides is determined by six (dihydro)ceramide synthase (CerS) isoforms. Previously, we and others showed that mutations in the major neuron-specific CerS1, which synthesizes 18-carbon fatty acyl (C 18 ) ceramide, cause elevation of long-chain base (LCB) substrates and decrease in C 18 ceramide and derivatives in the brain, leading to neurodegeneration in mice and myoclonus epilepsy with dementia in humans. Whether LCB elevation or C 18 ceramide reduction leads to neurodegeneration is unclear. Here, we ectopically expressed CerS2, a nonneuronal CerS producing C 22 -C 24 ceramides, in neurons of Cers1-deficient mice. Surprisingly, the Cers1 mutant pathology was almost completely suppressed. Because CerS2 cannot replenish C 18 ceramide, the rescue is likely a result of LCB reduction. Consistent with this hypothesis, we found that only LCBs, the substrates common for all of the CerS isoforms, but not ceramides and complex sphingolipids, were restored to the wild-type levels in the Cers2-rescued Cers1 mutant mouse brains. Furthermore, LCBs induced neurite fragmentation in cultured neurons at concentrations corresponding to the elevated levels in the CerS1-deficient brain. The strong association of LCB levels with neuronal survival both in vivo and in vitro suggests high-level accumulation of LCBs is a possible underlying cause of the CerS1 deficiency-induced neuronal death.sphingolipid | ceramide synthase | ceramide | long-chain base | neurodegeneration S phingolipids carry out essential functions in eukaryotes (1).The hydrophobic moiety of sphingolipids, called ceramide, is a fatty acylated long-chain base (LCB). LCBs can differ in their degree of saturation (e.g., sphingosine vs. dihydrosphingosine/ sphinganine) or hydroxylation (e.g., sphingosine vs. phytosphingosine) (2). LCBs and their phosphorylated derivatives are potent signaling molecules (3). Moreover, accumulation of aberrant deoxy-LCBs has recently been linked to hereditary sensory and autonomic neuropathy type 1 and taxane-induced peripheral neuropathy (4-6). Very high concentrations (100 μM) of regular LCBs are also toxic to cultured neurons (7,8). In addition, intoxication with fumonisin B1, a fungal ceramide synthase inhibitor causing elevation of LCBs and reduction of ceramides, leads to neural tube and neurological defects in humans and cattle (9). However, whether accumulation of regular LCBs in vivo or LCB treatment at physiologically relevant concentrations in vitro causes neuron death or damage has not been thoroughly investigated.The fatty acyl chain of ceramide can also vary in chain lengths, saturation, and hydroxylation (2). Emerging evidence suggests specific functions for different ceramide species. For instance, ceramide with a C 18 fatty acyl chain (C 18 ceramide) has been suggested to cause apoptosis in certain cancer cells, whereas ceramide with a C 16 ...

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“…CerS1-CerS6 act chain length specifically and introduce side chains to form C14-C26 ceramides. Thus, CerS1 synthesizes mainly C18-Cer, CerS4 synthesizes C18-/C20-Cer, CerS5 and CerS6 synthesize mostly C16-Cer, CerS2 synthesizes mainly C22-/C24-Cer, and CerS3 synthesizes very long chain ceramides (9). In addition to de novo synthesis, the salvage pathway also supplies ceramides mainly via the activation of sphingomyelinases (10).…”

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confidence: 99%

Ceramide Synthase 6 Plays a Critical Role in the Development of Experimental Autoimmune Encephalomyelitis

Schiffmann

Ferreiròs

Birod

et al. 2012

The Journal of Immunology

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Ceramides are mediators of apoptosis and inflammatory processes. In an animal model of multiple sclerosis (MS), the experimental autoimmune encephalomyelitis (EAE) model, we observed a significant elevation of C16:0-Cer in the lumbar spinal cord of EAE mice. This was caused by a transiently increased expression of ceramide synthase (CerS) 6 in monocytes/macrophages and astroglia. Notably, this corresponds to the clinical finding that C16:0-Cer levels were increased 1.9-fold in cerebrospinal fluid of MS patients. NO and TNF-α secreted by IFN-γ–activated macrophages play an essential role in the development of MS. In murine peritoneal and mouse-derived RAW 264.7 macrophages, IFN-γ–mediated expression of inducible NO synthase (iNOS)/TNF-α and NO/TNF-α release depends on upregulation of CerS6/C16:0-Cer. Downregulation of CerS6 by RNA interference or endogenous upregulation of C16:0-Cer mediated by palmitic acid in RAW 264.7 macrophages led to a significant reduction or increase in NO/TNF-α release, respectively. EAE/IFN-γ knockout mice showed a significant delay in disease onset accompanied by a significantly less pronounced increase in CerS6/C16:0-Cer, iNOS, and TNF-α compared with EAE/wild-type mice. Treatment of EAE mice with l-cycloserine prevented the increase in C16:0-Cer and iNOS/TNF-α expression and caused a remission of the disease. In conclusion, CerS6 plays a critical role in the onset of MS, most likely by regulating NO and TNF-α synthesis. CerS6 may represent a new target for the inhibition of inflammatory processes promoting MS development.

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The Role of the Ceramide Acyl Chain Length in Neurodegeneration: Involvement of Ceramide Synthases

Cited by 121 publications

References 56 publications

LRRK2 deficiency impacts ceramide metabolism in brain

LRRK2 deficiency impacts ceramide metabolism in brain

Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

Ceramide Synthase 6 Plays a Critical Role in the Development of Experimental Autoimmune Encephalomyelitis

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