Exploring Sphingolipid Implications in Neurodegeneration

Abstract

Over the past decade, it was found that relatively simple sphingolipids, such as ceramide, sphingosine, sphingosine-1-phosphate, and glucosylceramide play important roles in neuronal functions by regulating rates of neuronal growth and differentiation. Homeostasis of membrane sphingolipids in neurons and myelin is essential to prevent the loss of synaptic plasticity, cell death and neurodegeneration. In our review we summarize data about significant brain cell alterations of sphingolipids in different neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, Amyotrophic Lateral Sclerosis, Gaucher's, Farber's diseases, etc. We reported results obtained in brain tissue from both animals in which diseases were induced and humans in autopsy samples. Moreover, attention was paid on sphingolipids in biofluids, liquor and blood, from patients. In Alzheimer's disease sphingolipids are involved in the processing and aggregation of β-amyloid and in the transmission of the cytotoxic signal β-amyloid and TNFα-induced. Recently, the gangliosides metabolism in transgenic animals and the relationship between blood sphingolipids changes and cognitive impairment in Alzheimer's disease patients have been intensively studied. Numerous experiments have highlighted the involvement of ceramide and monohexosylceramide metabolism in the pathophysiology of the sporadic forms of Parkinson's disease. Moreover, gene mutations of the glucocerebrosidase enzyme were considered as responsible for Parkinson's disease via transition of the monomeric form of α-synuclein to an oligomeric, aggregated toxic form. Disturbances in the metabolism of ceramides were also associated with the appearance of Lewy's bodies. Changes in sphingolipid metabolism were found as a manifestation of Amyotrophic Lateral Sclerosis, both sporadic and family forms, and affected the rate of disease development. Currently, fingolimod (FTY720), a sphingosine-1-phosphate receptor modulator, is the only drug undergoing clinical trials of phase II safety for the treatment of Amyotrophic Lateral Sclerosis. The use of sphingolipids as new diagnostic markers and as targets for innovative therapeutic strategies in different neurodegenerative disorders has been included.

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

“…Further analysis of these proteomic changes across age also provided insight on the mechanism(s) in which neurodegeneration occurs as result of PGRN deficiency. We identified novel proteins in the Grn −/− mouse proteome that are decreased at 3-months, which suggest an impairment of lysosomal metabolism of lipids, including sphingolipids, which are particularly important for neuronal survival [2,14]. Lysosomal dysregulation is exacerbated with age in the Grn −/− mouse brain leading to neuroinflammation, synaptic loss, and decreased markers of oligodendrocytes, myelin, and neurons.…”

Human breast milk as source of sphingolipids for newborns: comparison with infant formulas and commercial cow’s milk

“…Depending on the different Cer-synthase isoforms, from 1 to 6, Cers with different acyl chain lengths can be produced [ 2 ]. Cers can be phosphorylated to Cer-1-phosphate, can be converted to glycosphingolipid (GLS) or can be used to synthesize SM by SM-synthase that uses phosphatidylcholine as donor of phosphocholine group [ 3 ]. In turn, SM can be hydrolyzed by five sphingomyelinases, located in different subcellular fractions and activated at different pH, to produce Cer [ 3 ].…”

“…Cers can be phosphorylated to Cer-1-phosphate, can be converted to glycosphingolipid (GLS) or can be used to synthesize SM by SM-synthase that uses phosphatidylcholine as donor of phosphocholine group [ 3 ]. In turn, SM can be hydrolyzed by five sphingomyelinases, located in different subcellular fractions and activated at different pH, to produce Cer [ 3 ]. Cers produced from SM and GSL degradation in lysosomes are exported from these through specific proteins to reach again the Golgi apparatus where they are recycled and re-utilized in salvage processes [ 4 ].…”

Therapeutic implications and role of serum sphingolipids on psoriasis severity after narrow band ultraviolet B treatment: A cross sectional controlled study

“…Cermaides (CER) and sphingosine 1 phosphate (S1P) are among the most biologically active skin sphingolipids that modulate a number of cellular functions. 2 Ceramides represent the most abundant lipids by weight (50%) in the epidermal membrane. More than 11 classes of ceramides exist and exert action through induction of apoptotic signaling pathways or down signaling the survival pathways.…”