Reversal of pathologic changes in fibroblasts from Niemann-Pick type C disease patients by inhibition of bromodomain and extraterminal proteins

Inborn errors of lysosomal function often provoke disorders presenting highly variable onset, diverse visceral, neurologic and psychiatric symptoms and reduced life spans. A prime example is Niemann-Pick type C disease (NPCD). At present, therapeutic options are limited to palliative care and disease-modifying drugs, and there is a need for new treatments. Here, we explored bromodomain and extra-terminal domain (BET) proteins as a new drug target for NPCD using patient-derived skin fibroblasts. Treatment of cells with JQ1, a prototype BET protein inhibitor, enhanced the level of NPC1 protein, diminished lysosomal expansion and cholesterol accumulation, and induced extracellular release of lysosomal components in a dose- and time-dependent manner. The effect of JQ1 on protein levels was largely independent from the patient line tested, but the extent of cholesterol reduction varied in a line-dependent manner. Lastly, JQ1 enhanced and reduced cholesterol accumulation induced by inhibition of NPC1 activity and of histone deacetylases, respectively. Taken together, our results provide further evidence for epigenetic regulation of cellular NPC1 levels and cholesterol homeostasis. Pharmacologic inhibition of bromodomain proteins should be explored as candidate therapeutic approach for NPCD and as a tool to understand basic mechanisms of lysosomal function and lipid metabolism.