Restoration of lysosomal membrane integrity in cell models of Pompe disease depends on fatty acid synthase and its product palmitic acid

Lysosomal storage disorders (LSDs) are rare inherited diseases caused by mutations in lysosomal proteins, leading to substrate accumulation and lysosomal dysfunction. Whether this build-up compromises lysosomal membrane integrity remains an open question. In this study, we aimed to investigate the presence of lysosomal membrane damage in LSD cells and to identify mechanisms that could reveal potential therapeutic strategies for amelioration of cellular physiology. Methods: Primary skin fibroblasts from Pompe disease patients were used to evaluate lysosomal integrity and function. Pharmacologic and metabolite treatments were applied in loss-of-function and rescue analyses, and transcriptomics analysis was done under these conditions. Results: In Pompe disease, caused by mutations in the acid alpha-glucosidase gene, glycogen accumulation, palmitate treatment improved lysosomal function in fibroblasts from patients, with no significant effect at transcriptional level. Conclusions: These findings open to novel therapeutic opportunities for improvement of lysosomal function through development of treatments that target fatty acid metabolism.