The Causes Of Lysosomal Diseases

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More dysregulated metabolites were identified in the liver (n=177) than that in the brain (n=122). Notably, there are more amino acid, amino acid derivatives and dipeptides identified in livers (mostly upregulated). These results are expected because the liver is the primary site of metabolism. In terms of pathways enriched, significant involvement of neurotransmission and chemical synaptic transmission were observed in the brain. Meanwhile, there are several pathways only enriched in livers, including gamma glutamyl cycle, leukotriene biosynthesis, Phase II conjugation and glutathione synthesis, which are mainly associated with oxidative stress and inflammation. The energy imbalance in SD leads to increased respiratory chain activity in …show more content…

The oxidative stress can cause cell damage, resulting in inflammation, which has also been found to be a major contributor to disease progression of GM2 gangliosidosis [17]. In this study, we identified elevation in glutathione pathways, which plays a pivotal role in responses to oxidative stress. Another evidence of inflammation is reduced levels of arachidonic acid, an omega-6 fatty acid, in brain samples of SD mice. Oxidation of arachidonic acid can generate leukotrienes, a family of eicosanoid inflammatory mediators produced in leukocytes, and thus promote inflammation. The increased energy requirements can also activate autophagy and protein catabolism, which have been found in MPS I and MPS VII mice [13]. In this study, we found increased levels of amino acids, amino acid derivatives and dipeptides, indicating increased protein catabolism. Increased requirements of energy and raw materials can also activate lipid metabolism and carbohydrate metabolism, manifested by decreased adiposity, a common observation in many lysosomal diseases [18-20]. In addition, the enlarged lysosome and distended cells due to abnormal accumulation requires increased membrane synthesis, which can also affect lipid metabolism. Our previous proteomic analysis [21] also identified abnormality in the cytoskeleton system, which can be partially attributed to altered cellular architecture due to storage accumulation. Collectively, we show here that the energy imbalance caused by the lack of

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