The use of genistein and ambroxol is an effective approach in correcting cellular dysfunctions of mucopolysaccharidosis-plus syndrome

Mucopolysaccharidosis-plus syndrome (MPS plus or MPSPS) is an ultrarare inherited metabolic disease, caused by mutations in the VPS33A gene. Like in different types of mucopolysaccharidosis (MPS), glycosaminoglycan (GAG) storage in cells of patients is evident. However, unlike MPS, the genetic defects in MPSPS cause impairment in the VPS33A protein level rather than inactivation of lysosomal hydrolases responsible for GAG degradation. Recent works demonstrated that low abundance of mutated VPS33A causes defective endosomal trafficking, resulting in poor delivery of GAGs (and perhaps also other compounds) to lysosomes, preventing their effective turnover. Here, we tested the hypothesis that impairment of protein degradation machineries, proteasomes by genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)-4 H -1-benzopyran-4-one) and endoplasmic-reticulum-associated protein degradation (ERAD) by ambroxol (4-((2-amino-3,5-dibromophenyl)methylamino) cyclohexan-1-ol), might result in elevation of levels of the mutated, partially active VPS33A and restoration of endosomal trafficking. Using MPSPS patient-derived fibroblasts, we demonstrated that treatment with genistein and ambroxol resulted in elevation of the mutant VPS33A protein level, as well as in improvement or correction of various previously reported cellular defects, including GAG levels, endosomal markers, and cytoskeleton elements. In the light of these results, and since both genistein and ambroxol were previously demonstrated to be safe when used in relatively high amounts, we propose that the use of these compounds, and especially their combination, can be considered as a potential therapeutic approach in MPSPS, which is currently an incurable disease.