LIMES, Kekulé-Institut, 53121 Bonn, Germany.
J Neurosci. 2013 Jun 19;33(25):10195-208. doi: 10.1523/JNEUROSCI.0822-13.2013.
Gangliosides are the main glycolipids of neuronal plasma membranes. Their surface patterns are generated by coordinated processes, involving biosynthetic pathways of the secretory compartments, catabolic steps of the endolysosomal system, and intracellular trafficking. Inherited defects in ganglioside biosynthesis causing fatal neurodegenerative diseases have been described so far almost exclusively in mouse models, whereas inherited defects in ganglioside catabolism causing various clinical forms of GM1- and GM2-gangliosidoses have long been known. For digestion, gangliosides are endocytosed and reach intra-endosomal vesicles. At the level of late endosomes, they are depleted of membrane-stabilizing lipids like cholesterol and enriched with bis(monoacylglycero)phosphate (BMP). Lysosomal catabolism is catalyzed at acidic pH values by cationic sphingolipid activator proteins (SAPs), presenting lipids to their respective hydrolases, electrostatically attracted to the negatively charged surface of the luminal BMP-rich vesicles. Various inherited defects of ganglioside hydrolases, e.g., of β-galactosidase and β-hexosaminidases, and of GM2-activator protein, cause infantile (with tetraparesis, dementia, blindness) and different protracted clinical forms of GM1- and GM2-gangliosidoses. Mutations yielding proteins with small residual catabolic activities in the lysosome give rise to juvenile and adult clinical forms with a wide range of clinical symptomatology. Apart from patients' differences in their genetic background, clinical heterogeneity may be caused by rather diverse substrate specificities and functions of lysosomal hydrolases, multifunctional properties of SAPs, and the strong regulation of ganglioside catabolism by membrane lipids. Currently, there is no treatment available for neuronal ganglioside storage diseases. Therapeutic approaches in mouse models and patients with juvenile forms of gangliosidoses are discussed.
神经节苷脂是神经元质膜的主要糖脂。它们的表面模式是通过协调的过程产生的，涉及分泌区室的生物合成途径、内溶酶体系统的分解代谢步骤和细胞内运输。迄今为止，导致致命神经退行性疾病的神经节苷脂生物合成遗传缺陷在小鼠模型中已被描述，但导致各种 GM1 和 GM2 神经节苷脂贮积症的神经节苷脂分解代谢遗传缺陷早已为人所知。为了消化，神经节苷脂被内吞并到达内体小泡。在晚期内体水平，它们耗尽了稳定膜的脂质，如胆固醇，并富含双（单酰基甘油）磷酸（BMP）。溶酶体分解代谢在酸性 pH 值下由阳离子神经鞘脂激活蛋白（SAP）催化，将脂质呈递给各自的水解酶，通过静电吸引到富含 BMP 的腔内腔小泡的负电荷表面。各种神经节苷脂水解酶的遗传缺陷，例如β-半乳糖苷酶和β-己糖胺酶，以及 GM2-激活蛋白，导致婴儿期（伴有四肢瘫痪、痴呆、失明）和不同迁延性 GM1 和 GM2 神经节苷脂贮积症的临床形式。在溶酶体中产生具有小残留分解代谢活性的蛋白质的突变导致具有广泛临床症状的青少年和成年临床形式。除了患者在遗传背景上的差异外，临床异质性可能是由于溶酶体水解酶的底物特异性和功能、SAP 的多功能特性以及膜脂质对神经节苷脂分解代谢的强烈调节而引起的。目前，神经元神经节苷脂贮积病尚无治疗方法。讨论了在小鼠模型和青少年神经节苷脂贮积症患者中使用的治疗方法。
