Linking Enzyme Upregulation to Autophagic Failure: A Potential Biomarker for GM1 Gangliosidosis

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 {beta}-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 {beta}-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.