Abstract
Niemann-Pick type C (NPC) disease is a neurovisceral atypical lipid storage disorder involving the accumulation of cholesterol and other lipids in the late endocytic pathway. The pathogenic mechanism that links the accumulation of intracellular cholesterol with cell death in NPC disease in both the CNS and the liver is currently unknown. Oxidative stress has been observed in the livers and brains of NPC mice and in different NPC cellular models. Moreover, there is evidence of an elevation of oxidative stress markers in the serumof NPC patients. Recent evidence strongly suggests that mitochondrial dysfunction plays an important role in NPC pathogenesis and that mitochondria could be a significant source of oxidative stress in this disease. In this context, the accumulation of vitamin E in the late endosomal/lysosomal compartments in NPC could lead to a potential decrease of its bioavailability and could be another possible cause of oxidative damage. Another possible source of reactive species in NPC is the diminished activity of different antioxidant enzymes. Moreover, because NPC is mainly caused by the accumulation of free cholesterol, oxidized cholesterol derivatives produced by oxidative stress may contribute to the pathogenesis of the disease.
Highlights
Niemann-Pick type C disease (NPC) is a neurovisceral atypical lipid storage disorder that is mainly characterized by unesterified cholesterol accumulation in late endosomal/ lysosomal (LE/Lys) compartments [1]
The central nervous system (CNS) is especially sensitive to oxidative stress damage [22]. This sensitivity can be explained by several features of the CNS: the high concentration of polyunsaturated fatty acids that are susceptible to lipid peroxidation, the relatively large amounts of oxygen consumed for energy production, and the fewer antioxidant defenses available to the CNS compared with other organs
Highlighting the role of oxidative stress in NPC, we have shown that treatment with the antioxidant N-Acetyl Cysteine (NAC) prevented c-Abl/p73 activation and apoptosis in NPC-like neurons, suggesting that oxidative stress is the main upstream stimulus activating the c-Abl/p73 pathway in NPC neurons [26]
Summary
Niemann-Pick type C disease (NPC) is a neurovisceral atypical lipid storage disorder that is mainly characterized by unesterified cholesterol accumulation in late endosomal/ lysosomal (LE/Lys) compartments [1]. The Npc gene encodes a soluble lysosomal protein that binds cholesterol [12] with a 1 : 1 stoichiometry and submicromolar affinity [13, 14]. Oxidative Medicine and Cellular Longevity supranuclear ophthalmoplegia, and its other prominent neurologic features include cataplexy, dysarthria, dysphagia, dystonia, and seizures [18, 19] These symptoms are associated with damage to the central nervous system (CNS), especially in the cerebellum, where extensive and progressive neuronal death is observed [20]. Oxidative damage is present in animal and cellular NPC models and in NPC patients; it may have a relevant role in the pathogenesis and progression of the disease
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