Ceramide, the precursor of all complex sphingolipids, is a potent signaling molecule that mediates key events of cellular pathophysiology. In the nervous system, the sphingolipid metabolism has an important impact. Neurons are polarized cells and their normal functions, such as neuronal connectivity and synaptic transmission, rely on selective trafficking of molecules across plasma membrane. Sphingolipids are abundant on neural cellular membranes and represent potent regulators of brain homeostasis. Ceramide intracellular levels are fine-tuned and alteration of the sphingolipid–ceramide profile contributes to the development of age-related, neurological and neuroinflammatory diseases. The purpose of this review is to guide the reader towards a better understanding of the sphingolipid–ceramide pathway system. First, ceramide biology is presented including structure, physical properties and metabolism. Second, we describe the function of ceramide as a lipid second messenger in cell physiology. Finally, we highlight the relevance of sphingolipids and ceramide in the progression of different neurodegenerative diseases.

Background:The Goodpasture antigen-binding protein (GPBP) and serum amyloid P component (SAP) bind to type IV collagen and are found in plasma. Results: GPBP binds to human SAP. Conclusion: GPBP and SAP form complexes under physiological and pathological conditions. Significance: This interaction might be involved in protein aggregation in Alzheimer disease and the resulting innate immune response.

The Goodpasture antigen-binding protein (GPBP) and its splice variant the ceramide transporter (CERT) are multifunctional proteins that have been found to play important roles in brain development and biology. However, the function of GPBP and CERT is controversial because of their involvement in two apparently unrelated research fields: GPBP was initially isolated as a protein associated with collagen IV in patients with the autoimmune disease Goodpasture syndrome. Subsequently, a splice variant lacking a serine-rich domain of 26 amino acids (GPBPD26) was found to mediate the cytosolic transport of ceramide and was therefore (re)named CERT. The two splice forms likely carry out different functions in specific sub-cellular localizations. Selective GPBP knockdown induces extensive apoptosis and tissue loss in the brain of zebrafish. GPBP/GPBPD26 knockout mice die as a result of structural and functional defects in endoplasmic reticulum and mitochondria. Because both mitochondria and ceramide play an important role in many biological events that regulate neuronal differentiation, cellular senescence, proliferation and cell death, we propose that GPBP and CERT are pivotal in neurodegenerative processes. In this review, we discuss the current state of knowledge on GPBP and CERT, including the molecular and biochemical characterization of GPBP in the field of autoimmunity as well as the fundamental research on CERT in ceramide transport, biosynthesis, localization, metabolism and cell homeostasis. Keywords: autoimmunity, ceramide, GPBP/CERT, neurodegenerative diseases. J. Neurochem. (2010) 113, 1369-1386. | 2010 | 113 | 1369-1386 doi: 10.1111/j.1471-4159.2010 (Raya et al. 1999). Goodpasture's syndrome is a strictly human disorder caused by antibodies directed against the non-collagenous domain of the a3-chain of collagen type IV [a3 (IV) NCI]. Collagen is a major component of the extracellular matrix. The autoantibodies cause rapid functional disruption of the basement membrane of lungs, kidneys and the choroid plexus (Salama et al. 2001). GPBP is a soluble extracellular protein which binds and phosphorylates the antigen in this syndrome. Its expression is increased in other spontaneous autoimmune disorders including Goodpasture's syndrome, lupus erythematosus, pemphigoid and lichen planus (Raya et al. 2000), suggesting that GPBP might be an important protein in autoimmune disorders, where autoantigens arise from abnormal protein domain organization. JOURNAL OF NEUROCHEMISTRYSubsequently, in 2003, Hanada and colleagues showed that a spliced variant of GPBP which lacks a serine-rich domain composed of 26 aa residues was responsible for the cytosolic trafficking of ceramide from the endoplasmic reticulum (ER), to the Golgi apparatus. Hence, this isoform was termed as CERT (Hanada et al. 2003). Since the longer isoform also has ceramide transport properties in vitro, GPBP was renamed as CERT L (Hanada et al. 2003).Thus far it is not clear how the extracellular function of GPBP/CERT L , which is related to immu...

SummaryNeuronal polarity in the developing cortex begins during the early stages of neural progenitor migration toward the cortical plate and culminates with the specification of the axon and dendrites. Here, we demonstrate that the Ran-dependent nucleocytoplasmic transport machinery is essential for the establishment of cortical neuron polarity. We found that Ran-binding protein 1 (RanBP1) regulates axon specification and dendritic arborization in cultured neurons in vitro and radial neural migration in vivo. During axonogenesis, RanBP1 regulates the cytoplasmic levels of the polarity protein LKB1/Par4, and this is dependent on the nuclear export machinery. Our results show that downstream of RanBP1, LKB1 function is mediated by the STK25-GM130 pathway, which promotes axonogenesis through Golgi regulation. Our results indicate that the nucleocytoplasmic transport machinery is a main regulator of neuron polarity, including radial migration, and that the regulated export of LKB1 through RanBP1 is a limiting step of axonogenesis.