Sialidosis is an autosomal recessive disorder caused by a dysfunctional Sialidase enzyme. Categorised into two phenotypes, Sialidosis type I and II, Sialidosis is a highly heterogeneous disorder with varying ages of onset and pathologies. Currently, there is no viable therapy for the treatment of Sialidosis patients. At the molecular level, cells from Sialidosis patients with compound heterozygous mutations show improper enzyme folding, loss of Sialidase enzyme activity and subsequent accumulation of sialylconjugates within lysosomes. One promising treatment option is the use of small pharmacological molecules to increase the enzymatic activities of mutant proteins. In this study, we examined the efficacy of the immuno-suppressant (Celastrol) as well as a proteosomal inhibitor (MG132) to rescue mutant enzymes with altered conformation. Our results reveal that MG132 enhances enzyme activity and its localisation in cells expressing defective Sialidase. We also found that MG132 reduces accumulation of ganglioside products, GT1b, GD3, and GM3 in pre-loaded Sialidosis cells. Alternatively, Celastrol appears to reduce Sialidase expression and activity revealing a potentially novel effect of Celastrol on Sialidase. Interestingly, the combination of Celastrol and MG132 appears to amplify the beneficial impact of MG132 on both the endogenous and recombinant expression of defective Sialidase. This study explores a novel biological criteria to assess the efficacy of small molecules through accumulation analysis and points to a potential therapeutic strategy for the treatment of Sialidosis.
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