Mechanistic insights into arimoclomol mediated effects on lysosomal function in Niemann-pick type C disease.

Niemann-Pick disease type C (NPC) is an ultra-rare, fatal neurodegenerative disease. It is characterized by lysosomal dysfunction with cytotoxic accumulation of unesterified cholesterol and glycosphingolipids in lysosomes, which causes neurodegeneration and peripheral organ dysfunction. Arimoclomol, an orally available small molecule, is the first FDA-approved treatment for NPC when used in combination with miglustat. Here, we present the results of a series of in vitro studies performed to explore the pathways by which arimoclomol targets the fundamentals of NPC etiology. While the precise cellular interactions of arimoclomol remain unclear, the increased translocation of the transcription factors EB and E3 (TFEB and TFE3) from the cytosol to the nucleus is a key initial step for triggering a cascade of downstream events that can rescue cellular functions. Activation of TFEB and TFE3 raises the expression rates of coordinated lysosomal expression and regulation (CLEAR) genes including NPC1 that are essential for the regulation of lysosomal function. The subsequent upregulation of CLEAR network proteins combined with increased unfolded protein response activation was shown to enlarge the pool of matured NPC1 capable of reaching the lysosome to reduce cholesterol accumulation. By also amplifying expression of CLEAR genes associated with autophagy, arimoclomol has the potential to act on different pathways and improve cell viability independent of NPC1 protein levels and functionality. In summary, the findings presented illustrate how arimoclomol improves lysosomal function and potentially autophagy flux to decrease lipid burden in NPC patient fibroblasts.