Role of Par-4 in ceramide-inducible effects in neurodegeneration

Recently, the idea that alterations in sphingolipids metabolism contribute to the pathogenesis of various neurodegenerative diseases has been gaining vast acceptance. Especially ceramide, the precursor of all complex sphingolipids, is thought to be a key sphingolipid metabolite and lipid second messenger. For several decades, research on sphingolipids related to neurodegenerative disease focused on myelin constituents and lipid storage diseases. However, recent advances in methods of mass spectrometric lipid analysis (lipidomics) have greatly advanced the knowledge of sphingolipids in neurodegenerative and psychiatric disorder. This was concomitant with the recognition of ceramide as a as key player in lipid cell signaling and regulation of cell death and survival. There is evidence that ceramide is invoked in a myriad of cellular processes related to neurodegeneration such as autophagy, ER stress, mitochondrial dysfunction, and exosome secretion which leads to neurotoxic protein spreading. However, it is still not clear which additional factors may interact with ceramide to determine the specific outcome of a particular ceramide-induced cell signaling pathway. Several studies have shown that interaction with prostate apoptosis 4 (PAR-4) regulates these cell signaling pathways, particularly for the induction of neuronal apoptosis during neurodegenerative disease. We will discuss the function of PAR-4 in the regulation of ceramide neurotoxicity and neuronal apoptosis induced by intrinsic ceramide and PAR-4/ceramide originating in other cells and transported to neurons via extracellular vesicles.