Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, 72 King William Road, North Adelaide 5006, Australia.
Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, 72 King William Road, North Adelaide 5006, Australia; School of Medicine, University of Adelaide, Adelaide 5005, Australia.
Mol Genet Metab. 2020 Feb;129(2):111-116. doi: 10.1016/j.ymgme.2019.08.008. Epub 2019 Aug 29.
Gangliosides are complex glycosphingolipids that are vital for proper brain development and function. Alterations in ganglioside metabolism are evident in neurological disorders including the inherited metabolic disease mucopolysaccharidosis type IIIA (MPS IIIA/Sanfilippo A syndrome). Here we sought to comprehensively analyse alterations in ganglioside metabolism within the brain of a naturally occurring MPS IIIA mouse model at early (one month) and late (six months of age) stages of disease progression, as well as the impact on related sphingolipids in the ganglioside metabolic pathway. The simple gangliosides G and G were elevated in the brain stem, cerebellum and sub-cortex of the MPS IIIA mouse at one month of age, but not in the cortex. By six months accumulation was significant throughout the brain, with G gangliosides also elevated. Elevations in other sphingolipids were limited to the upstream synthetic precursors, ceramide and dihexosylceramide (DHC) species containing 18:0 and 20:0 acyl chains, likely due to the abundance of these fatty acids in the elevated gangliosides. In contrast, sphingomyelin, sulphatide and DHC containing a 24:1 fatty acid, were all decreased in the brain stem of the MPS IIIA mice, suggestive of alterations in myelination. These perturbations in sphingolipid metabolism could provide an avenue for therapeutic intervention by manipulation with specific drugs that target the production of these lipids.
神经节苷脂是复杂的糖鞘脂，对于大脑的正常发育和功能至关重要。神经节苷脂代谢的改变在包括遗传性代谢疾病粘多糖贮积症 IIIA 型（MPS IIIA/Sanfilippo A 综合征）在内的神经紊乱中很明显。在这里，我们试图在疾病进展的早期（一个月）和晚期（六个月）全面分析天然发生的 MPS IIIA 小鼠模型大脑中的神经节苷脂代谢改变，以及对神经节苷脂代谢途径中相关神经鞘脂的影响。在 MPS IIIA 小鼠一个月大时，脑干、小脑和皮质下脑区的简单神经节苷脂 G 和 G 升高，但皮质中没有升高。到六个月时，积累在整个大脑中都很明显，G 神经节苷脂也升高了。其他神经鞘脂的升高仅限于上游合成前体，含有 18:0 和 20:0 酰基链的神经酰胺和二己糖神经酰胺（DHC）物质，这可能是由于升高的神经节苷脂中这些脂肪酸的丰富度。相比之下，MPS IIIA 小鼠脑干中的神经鞘磷脂、硫酸酯和含有 24:1 脂肪酸的 DHC 都减少了，提示髓鞘发生了改变。这些神经鞘脂代谢的紊乱可能为通过针对这些脂质产生的特定药物的操作提供治疗干预的途径。
