Abstract：
Biallelic variants in the SPG11 gene account for the most common form of autosomal recessive hereditary spastic paraplegia characterized by motor and cognitive impairment, with currently no therapeutic option. We previously observed in a Spg11 knockout mouse that neurodegeneration is associated with accumulation of gangliosides in lysosomes. To test whether a substrate reduction therapy could be a therapeutic option, we downregulated the key enzyme involved in ganglioside biosynthesis using an AAV-PHP.eB viral vector expressing a miRNA targeting St3gal5. Downregulation of St3gal5 in Spg11 knockout mice prevented the accumulation of gangliosides, delayed the onset of motor and cognitive symptoms, and prevented the upregulation of serum levels of neurofilament light chain, a biomarker widely used in neurodegenerative diseases. Importantly, similar results were observed when Spg11 knockout mice were administrated venglustat, a pharmacological inhibitor of glucosylceramide synthase expected to decrease ganglioside synthesis. Downregulation of St3gal5 or venglustat administration in Spg11 knockout mice strongly decreased the formation of axonal spheroids, previously associated with impaired trafficking. Venglustat had similar effect on cultured human SPG11 neurons. In conclusion, this work identifies the first disease-modifying therapeutic strategy in SPG11, and provides data supporting its relevance for therapeutic testing in SPG11 patients.
摘要：
SPG11基因中的双等位基因变异是最常见的常染色体隐性遗传性痉挛性截瘫，其特征是运动和认知障碍。目前没有治疗选择。我们先前在Spg11敲除小鼠中观察到神经变性与神经节苷脂在溶酶体中的积累有关。为了测试底物减少疗法是否可以作为治疗选择，我们使用AAV-PHP下调了参与神经节苷脂生物合成的关键酶。表达靶向St3gal5的miRNA的eB病毒载体。St3gal5在Spg11敲除小鼠中的下调阻止了神经节苷脂的积累,延迟了运动和认知症状的发作，并防止了神经丝轻链血清水平的上调，广泛用于神经退行性疾病的生物标志物。重要的是,当Spg11敲除小鼠服用venglustat时，观察到类似的结果，葡萄糖神经酰胺合成酶的药物抑制剂，有望减少神经节苷脂的合成。在Spg11敲除小鼠中下调St3gal5或venglustat给药强烈减少轴突球体的形成，以前与受损的贩运有关。Venglustat对培养的人SPG11神经元具有相似的作用。总之,这项工作确定了SPG11中的第一个疾病改善治疗策略,并提供了支持其与SPG11患者治疗性测试相关性的数据.
