Sphingolipids in neurodegenerative diseases

Abstract

Neurodegenerative Diseases (NDDs) are a group of disorders that cause progressive deficits of neuronal function. Recent evidence argues that sphingolipid metabolism is affected in a surprisingly broad set of NDDs. These include some lysosomal storage diseases (LSDs), hereditary sensory and autonomous neuropathy (HSAN), hereditary spastic paraplegia (HSP), infantile neuroaxonal dystrophy (INAD), Friedreich’s ataxia (FRDA), as well as some forms of amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). Many of these diseases have been modeled in Drosophila melanogaster and are associated with elevated levels of ceramides. Similar changes have also been reported in vertebrate cells and mouse models. Here, we summarize studies using fly models and/or patient samples which demonstrate the nature of the defects in sphingolipid metabolism, the organelles that are implicated, the cell types that are initially affected, and potential therapeutics for these diseases.

Loss of dihydroceramide desaturase drives neurodegeneration by disrupting endoplasmic reticulum and lipid droplet homeostasis in glial cells

“…Following its synthesis, CERT transports ceramide from the ER to the Golgi, but CERT is less efficient at transporting dihydroceramide than ceramide. 13 The expanded nature of the ER in ifc mutant larvae supports a model in which loss of ifc triggers excessive accumulation and retention of dihydroceramide in the ER, driving ER expansion and glial swelling. If this model is correct, reduction of dihydroceramide levels should suppress the ifc CNS phenotype.…”

“…The de novo ceramide biosynthetic pathway is well conserved among higher metazoans. 4,10,11,12,13 De novo ceramide synthesis occurs in the endoplasmic reticulum (ER) and starts with the rate-limiting activity of the serine palmitoyltransferase (SPT) complex, which condenses serine and palmitoyl-CoA (lauoryl-CoA in flies) to form 3-Ketosphinganine, which is converted to sphinganine by 3-Ketosphinganine reductase. Ceramide synthases condense sphinganine with acyl-CoA to generate dihydroceramide, which is converted to ceramide by dihydroceramide desaturases.…”

“…A hotspot for human neurodegenerative disease, the sphingolipid metabolic pathway is well conserved in higher metazoans (Fryst et al, 2004; Acharya & Acharya, 2005; Hannun & Obeid, 2018; Dunn et al, 2019; Pan et al, 2023). De novo ceramide synthesis occurs in the endoplasmic reticulum (ER) and starts with the rate-limiting condensation of serine and palmitoyl-CoA (or lauoryl-CoA in flies) by the serine palmitoyltransferase (SPT) complex to form 3-Ketosphinganine, which is converted to sphinganine by 3-Ketosphinganine reductase.…”

APOE genotype dictates lipidomic signatures in primary human hepatocytes

“…Interestingly, we noted that higher APOE levels were associated with lower levels of sphingolipids (Cer, LacCer, and dhSer), LPEp, NSer, and BMP. Sphingolipids have recently been implicated in cancer ( 99 ), metabolic disorders ( 100 ), as well as neurodegenerative diseases ( 101 ) with LacCer in particular related to inflammation in neurological disorders ( 102 ). Hence, that hepatic APOE levels may have predictive value for these sphingolipids is intriguing.…”

Glycosphingolipids in human parasites

“…The de novo pathway of ceramide biosynthesis in animal cells involves the generation of the sphingoid base, a type of sphingosine, which is derived from palmitoyl CoA through the condensation with serine (Fig. 1 ) [ 11 , 12 , 13 ]. This generates dehydrosphingosine which is then converted to dihydrosphingosine (also called sphinganine).…”