Research Laboratory, Oral Medicine Department, University of Sevilla, 41009 Sevilla, Spain.
Centro Andaluz de Biologia del Desarrollo (CABD, UPO-CSIC-JA), Facultad de Ciencias Experimentales (Área de Genética), Universidad Pablo de Olavide, 41013 Sevilla, Spain.
Cells. 2021 Nov 11;10(11):3122. doi: 10.3390/cells10113122.
Tay-Sachs and Sandhoff diseases (GM2 gangliosidosis) are autosomal recessive disorders of lysosomal function that cause progressive neurodegeneration in infants and young children. Impaired hydrolysis catalysed by β-hexosaminidase A (HexA) leads to the accumulation of GM2 ganglioside in neuronal lysosomes. Despite the storage phenotype, the role of autophagy and its regulation by mTOR has yet to be explored in the neuropathogenesis. Accordingly, we investigated the effects on autophagy and lysosomal integrity using skin fibroblasts obtained from patients with Tay-Sachs and Sandhoff diseases.
Pathological autophagosomes with impaired autophagic flux, an abnormality confirmed by electron microscopy and biochemical studies revealing the accelerated release of mature cathepsins and HexA into the cytosol, indicating increased lysosomal permeability. GM2 fibroblasts showed diminished mTOR signalling with reduced basal mTOR activity. Accordingly, provision of a positive nutrient signal by L-arginine supplementation partially restored mTOR activity and ameliorated the cytopathological abnormalities.
Our data provide a novel molecular mechanism underlying GM2 gangliosidosis. Impaired autophagy caused by insufficient lysosomal function might represent a new therapeutic target for these diseases.
We contend that the expression of autophagy/lysosome/mTOR-associated molecules may prove useful peripheral biomarkers for facile monitoring of treatment of GM2 gangliosidosis and neurodegenerative disorders that affect the lysosomal function and disrupt autophagy.
泰萨二氏症和桑德霍夫病（GM2 神经节苷脂贮积症）是溶酶体功能的常染色体隐性遗传病，可导致婴儿和幼儿进行性神经退行性变。β-己糖胺酶 A（HexA）水解作用受损导致 GM2 神经节苷脂在神经元溶酶体中积累。尽管存在储存表型，但自噬及其受 mTOR 调控的作用在神经发病机制中的作用尚未得到探索。因此，我们使用从泰萨二氏症和桑德霍夫病患者中获得的皮肤成纤维细胞研究了自噬和溶酶体完整性的影响。
病理性自噬体具有受损的自噬流，电镜和生化研究证实自噬流异常，表明溶酶体通透性增加，加速成熟组织蛋白酶和 HexA 释放到细胞质中。GM2 成纤维细胞显示出减少的 mTOR 信号传导，基础 mTOR 活性降低。因此，通过 L-精氨酸补充提供阳性营养信号部分恢复了 mTOR 活性并改善了细胞病理异常。
我们的数据提供了 GM2 神经节苷脂贮积症的新分子机制。溶酶体功能不足引起的自噬受损可能代表这些疾病的新治疗靶点。
我们认为，自噬/溶酶体/mTOR 相关分子的表达可能成为 GM2 神经节苷脂贮积症和影响溶酶体功能和破坏自噬的神经退行性疾病治疗的简便监测的有用外周生物标志物。
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