Mind the gatekeeper: key role of NPC1 protein and lysosomal cholesterol in metabolic diseases and therapeutical implications

NPC1 disease is caused by genetic mutations that compromise the function of NPC1 protein, a lysosomal cholesterol efflux protein. Lysosomes are important cellular hubs, where internal and external molecules are broken down and sorted to their final cellular destination, so that they can be processed according to the cells’ needs. In NPC1 disease, the lack of a fully functional NPC1 protein disrupts the traffic of lysosomal cholesterol, leading to lysosomal cholesterol accumulation, inflammation, and life-threatening disease burden.
The main goal of this thesis was to investigate whether different therapeutic strategies, ranging from dietary interventions to immunization, can ameliorate lysosomal cholesterol accumulation, inflammation and NPC1 disease burden. Of note, lysosomal cholesterol accumulation also occurs in diseases such as liver and cardiovascular disease, atherosclerosis, Alzheimer’s disease, and several types of cancer. As such, the findings of this thesis have the potential of benefitting a wide array of patients.