Oxidative Stress: A Pathogenic Mechanism for Niemann-Pick Type C Disease

Figure 1

Oxidative stress as a pathogenic mechanism in Niemann-Pick C disease. NPC disease arises from deficiencies in one of two lysosomal proteins, NPC1 and NPC2, which are involved in the proper export of free cholesterol (CH) from lysosomes to different cellular compartments. Therefore, in NPC disease, free cholesterol accumulates inside the lysosomes and intracellular cholesterol transport is impaired. Remarkably, vitamin E also accumulates inside the lysosomes, possibly diminishing its bioavailability and decreasing the antioxidant capacity of the cell. Additionally, mitochondrial cholesterol is also increased, leading to a decrease in mGSH levels and diminishing mitochondria antioxidant capacity. In this scenario, there is an increase in mitochondrial ROS production and a decrease in ATP production. These two phenomena are well-known features of mitochondrial dysfunction. Furthermore, decreases of catalase activity and increases in ROS production inside the peroxisomes have been reported. In summary, in NPC disease, alterations in several different organelles, including lysosomes, mitocondria, and peroxisomes, along with disturbances in copper (Cu) transport, trigger oxidative stress damage, activating proapoptotic pathways and proapoptotic gene expression and inducing apoptotic cell death. Symbols: green up-arrows indicate increase or activation; red down-arrows indicate decrease or inhibition; bold black arrows represent multistep pathways; angled blue arrows indicate gene transcription activation.