Ingrid 't Hart

12 Chapter 1 1 Ganglio-series GSLs are mainly found in the nervous system, where they cover 10-12% of the lipid content. GM3-Cer is found in almost all �ssues in vertebrates and is the major ganglioside in serum. Comparison of a standard diet (SD) and a high-fat diet (HFD) in mice resulted in more GM3-Cer and a higher expression of ST3Gal5 in the HFD group. It was found that GM3-Cer downregulates the response of the insulin receptor to insulin and showed higher serum levels in diabetes type 2 pa�ents. 3,31 Accumula�on of GM2-Cer, as a result of deficiencies in the degrada�on enzymes beta-hexosaminidase A and B, can cause severe disorders such as Tay Sachs and Sandhoff disease. 32 GM1-Cer forms a main component in lipid ra�s and can therefore easily be detected by an�-GM1 an�bodies and cholera toxin B subunit. 33 Recent findings suggest that treatment with GM1-Cer can reduce symptoms Parkinson’s disease (PD). 34 Furthermore, GM1-Cer is strongly expressed on CD4+ T-cells and is known to be an important component in lipid ra�s involved in the T-cell interac�on with an�gen presen�ng cells (APCs). 31 While most gangliosides reside on the outer membranes of the cells, GD3-Cer has also been found on mitochondrial membranes, where it regulates apoptosis. 35 Four ganglio-series GSLs, GM1-Cer, GD1a- Cer, GD1b-Cer and GT1b-Cer, cover up to 97% of gangliosides in the brain. 36 GD1a-Cer and GT1b-Cer on axons form ligands for myelin-associated glycoprotein (MAG, Siglec-4). This interac�on is important for myelin stability, axon regenera�on and protec�on from toxic damage. 28 Overall, the major SGLs in animals are SM4, SM3, SM2 and SB1a, which are the sulfated analogs of GM4, GM3, GM2 and GD1a. SGLs are thought to act as ion barriers or traps on the membrane, thereby protec�ng the cell against high extracellular osmo�c concentra�ons. 8 Muta�ons in ST3Gal5 can cause deficiencies of a- and b-series gangliosides, resul�ng in e.g. slow brain growth, growth failure, blindness and deafness. 31,37,38 Maintenance of ST3Gal5 expression and knock-down of B4GalNT1 (GM2-cer/GD2-Cer synthase) did not cause loss of hearing and led to the sugges�on that GM3-Cer is important for organiza�on and func�on of auditory hair cells. 38 Mice with disrupted B4GalNT1 ini�ally showed normal development, but as they agedmale infer�lity, motor deficits and defects in myelina�on and axonal degenera�on were observed. 2,3,39 Furthermore, B4GalNT1 has been found to posi�vely regulate β-site cleavage by inhibi�ng BACE1 (β-site APP cleaving enzyme 1) protein degrada�on. An increase in amyloid precursor protein (APP) cleavage leads to amyloid-β aggrega�on and the forma�on of plaques: a main event in Alzheimer’s disease. 40 Mice deficient in ST8Sia1, lacking GD3-Cer and b-series gangliosides, have a normal life span and do not show developmental defects. However, disrup�on of both ST8Sia1 and B4GalNT1 result in GM3-only-mice, which showed extreme sound sensi�vi�es, lethal seizures or even sudden death. 41 Also, a gene�c study indicated a correla�on between ST8Sia1 variants and the development of mul�ple sclerosis (MS). 42 Knockdown of B3GalT4 reduces the main brain gangliosides, such as GM1a-Cer, resul�ng in different neurodegenera�ve diseases such as Parkinson’s. 43 While ST3Gal2 deficient mice appear normal, ST3Gal3 deficient mice are par�ally impaired and a double knockout of ST3Gal2 and -3 resulted in severely impaired mice at weaning. 28