With an increasing aging population, neurodegenerative diseases are having an increased impact on society. Typically, these diseases are diagnosed significantly past symptom onset, decreasing the possibility of effective treatment. A non-invasive biomarker and specific target are needed to diagnose and treat the disease before late-stage symptoms. GM1 Gangliosidosis is a lysosomal storage disease where lysosomal enzyme β-galactosidase is missing. As a result, GM1 ganglioside is not broken down and accumulates in the cell, ultimately leading to cell death. One of the main aspects of GM1 Gangliosidosis, and other neurodegenerative diseases, is impaired autophagy: reduced fusion of autophagosomes and lysosomes to degrade cellular waste. In this paper, we show that healthy cells (NSV3) have approximately 13 times more co-localization of lysosomes and autophagosomes than GM1 Gangliosidosis- diseased cells (GM1SV3), as demonstrated via immunofluorescence. GM1SV3 fold normal enzyme activity of β-galactosidase was downregulated while mannosidase, and hexosaminidase A were both upregulated. When inducing impaired autophagy in NSV3 via starvation, co-localization gradually decreases with increased starvation time. Most notably, after 48-hour starvation, healthy cells (NSV3) showed no significant difference in co-localization compared to GM1SV3. NSV3 under starvation conditions showed a significant increase between time starved and fold normal enzyme activity, with a positive correlation being observed. Activities of mannosidase, and hexosaminidase A of starved NSV3 closely resemble, and surpass, GM1SV3 after 12-hour starvation. These observations have the potential to expand the conversation regarding impaired autophagy as a potential biomarker for disease progression and diagnostics and as a treatment target.

中文翻译：

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将酶上调与自噬失败联系起来：GM1神经节病的潜在生物标志物。

随着人口老龄化，神经退行性疾病对社会的影响越来越大。通常，这些疾病在症状发作后就被诊断出来，从而降低了有效治疗的可能性。需要一种非侵入性的生物标志物和特定的靶标来诊断和治疗晚期症状之前的疾病。GM1神经节苷脂病是一种溶酶体贮积病，其中溶酶体酶β-半乳糖苷酶缺失。结果，GM1神经节苷脂没有被分解并在细胞中积累，最终导致细胞死亡。GM1神经节病和其他神经退行性疾病的主要方面之一是自噬受损：自噬体和溶酶体融合减少，降解细胞废物。在本文中，我们通过免疫荧光证明，健康细胞（NSV3）的溶酶体和自噬体的共定位比GM1神经节病病细胞（GM1SV3）高约13倍。GM1SV3的β-半乳糖苷酶的正常酶活性下调，而甘露糖苷酶和己糖胺酶A均上调。当通过饥饿诱导NSV3的自噬受损时，共定位会随着饥饿时间的增加而逐渐降低。最值得注意的是，饥饿48小时后，健康细胞（NSV3）与GM1SV3相比，共定位没有显着差异。在饥饿条件下，NSV3显示饥饿时间和正常酶活性的倍数之间显着增加，并观察到正相关。饥饿的NSV3中的甘露糖苷酶和己糖胺酶A的活性非常相似，甚至超过 饥饿12小时后的GM1SV3。这些观察结果有可能扩大关于自噬受损作为疾病进展和诊断的潜在生物标志物以及治疗目标的讨论。