Gangliosides are glycosphingolipids highly abundant in the nervous system, and carry most of the sialic acid residues in the brain. Gangliosides are enriched in cell membrane microdomains ("lipid rafts") and play important roles in the modulation of membrane proteins and ion channels, in cell signaling and in the communication among cells. The importance of gangliosides in the brain is highlighted by the fact that loss of function mutations in ganglioside biosynthetic enzymes result in severe neurodegenerative disorders, often characterized by very early or childhood onset. In addition, changes in the ganglioside profile (i.e., in the relative abundance of specific gangliosides) were reported in healthy aging and in common neurological conditions, including Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), stroke, multiple sclerosis and epilepsy. At least in HD, PD and in some forms of epilepsy, experimental evidence strongly suggests a potential role of gangliosides in disease pathogenesis and potential treatment. In this review, we will summarize ganglioside functions that are crucial to maintain brain health, we will review changes in ganglioside levels that occur in major neurological conditions and we will discuss their contribution to cellular dysfunctions and disease pathogenesis. Finally, we will review evidence of the beneficial roles exerted by gangliosides, GM1 in particular, in disease models and in clinical trials.

Brain cholesterol homeostasis is altered in Huntington’s disease (HD), a neurodegenerative disorder caused by the expansion of a CAG nucleotide repeat in the HTT gene. Genes involved in the synthesis of cholesterol and fatty acids were shown to be downregulated shortly after the expression of mutant huntingtin (mHTT) in inducible HD cells. Nuclear levels of the transcription factors that regulate lipid biogenesis, the sterol regulatory element-binding proteins (SREBP1 and SREBP2), were found to be decreased in HD models compared to wild-type, but the underlying causes were not known. SREBPs are synthesized as inactive endoplasmic reticulum-localized precursors. Their mature forms (mSREBPs) are generated upon transport of the SREBP precursors to the Golgi and proteolytic cleavage, and are rapidly imported into the nucleus by binding to importin β. We show that, although SREBP2 processing into mSREBP2 is not affected in YAC128 HD mice, mSREBP2 is mislocalized to the cytoplasm. Chimeric mSREBP2-and mSREBP1-EGFP proteins are also mislocalized to the cytoplasm in immortalized striatal cells expressing mHTT, in YAC128 neurons and in fibroblasts from HD patients. We further show that mHTT binds to the SREBP2/importin β complex required for nuclear import and sequesters it in the cytoplasm. As a result, HD cells fail to upregulate cholesterogenic genes under sterol-depleted conditions. These findings provide mechanistic insight into the downregulation of genes involved in the synthesis of cholesterol and fatty acids in HD models, and have potential implications for other pathways modulated by SREBPs, including autophagy and excitotoxicity.

The optimum temperature for the growth of porcine stable (PS) kidney cell line is 37 degrees C. We have adapted the cell line to grow at 40 degrees C. The original cell line grown at 37 degrees C has been denoted as PS-37, and the adapted new strain has been denoted as PS-40. Both the cell lines were screened for mycoplasma by Hoechst staining and tritiated uridine-uracil uptake and were found to be negative. Comparative characterization of PS-40 and its progenitor PS-37 cell line was done by using various parameters. The antigenic studies indicated that the new cell strain was not cross-contaminated with any other cell lines. It was observed that PS-40 cells were more fibroblastic with clean cytoplasm and appeared healthy. The growth of PS-40 cells was faster than the original cell line. The karyological study showed heteroploid chromosome number in PS-40 cells. The modal chromosome number of PS-40 cells was 58, whereas that of PS-37 cell line was 38. The lactic dehydrogenase isoenzyme pattern showed a cathodal shift of bands. The PS-40 cell strain could be cryopreserved and revived. The viability of PS-37 as well as PS-40 cell lines is in the range of 90-95%, and the growth characteristics of thawed cells showed six- to eightfold multiplications within 5 d. The virus susceptibility study revealed that the cytopathic effect was more profound and observed 1 d earlier in PS-40 cell line. Increased yields of Japanese encephalitis, Sindbis, and Semliki forest viruses were obtained by 1.8, 1.75, and 1.5 log plaque-forming units/ml, respectively. The yield of West Nile virus was, however, comparable to that in PS-37 cell line. Both the cell lines were refractory to Dengue viruses.