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

Abstract

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 ...

Role of 1‐Deoxysphingolipids in docetaxel neurotoxicity

“…Moreover, the use of anti‐GD2 antibody for a cancer immunotherapy has been shown to cause peripheral neuropathy (recently reviewed in (Patel & Spassieva, 2018). The focus of our study is the effect of docetaxel on 1‐deoxySL levels, which have been shown by others and by us to be neurotoxic (Guntert et al, 2016; Penno et al, 2010; Spassieva et al, 2016). Nevertheless, we do not exclude that taxanes, by up‐regulating SPT and ceramide levels, affect ganglioside metabolism as well, which could potentially also contribute to neurotoxicity.…”

Altered mRNA expression levels of the major components of sphingolipid metabolism, ceramide synthases and their clinical implication in colorectal cancer

“…Sphingolipid metabolism serves a critical role in mammalian cell growth arrest and survival (33). Accumulating evidence have demonstrated that CerS, a major component in sphingolipid metabolism (7), regulates various biological phenomenon, including apoptosis (34), cancer (17,35), ER stress (36), hepatopathy (37), hypoxia/re-oxygenation injury (38), lipid metabolism (39), neurodegeneration (40), and sensitivity to chemotherapeutic drugs and radiation (30). Although aberrant CerS expression is correlated with cell death and proliferation (10)(11)(12)(13)(14) in various types of cancer, much uncertainty remains regarding the dysregulated mRNA levels of CerS gene in CRC and the clinical implications of this.…”

Ceramide synthesis regulates T cell activity and GVHD development

“…These data are consistent with distinct functions of ceramides with various different fatty acid chain lengths generated by CerS1-CerS6 (31). For example, while CerS2/ C24-ceramide is implicated in the regulation of liver function (32), CerS1-generated C18-ceramide is associated with nervous system physiology and function through the regulation of Purkinje cells (33). CerS3- Significance was determined by Student's t test.…”