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

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.

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

“…Thus, glucose metabolism appears to be affected at early stages of NPC disease. Markers of oxidative stress are also increased in brains of human NPC patients and animal models ( 36,37,67 ).…”

“…Thus, although cholesterol accumulates in LEs/Ls, there is a defi cit of cholesterol in the ER so that the sterol response element-binding protein (SREBP) pathway ( 33 ) is enhanced, and the synthesis and uptake of cholesterol are increased ( 9,34 ). The impaired traffi cking of cholesterol in NPC-defi cient cells profoundly affects multiple cellular functions such as regulation of lysosomal calcium homeostasis ( 35 ), oxidative stress ( 36,37 ), and vesicle traffi cking pathways mediated by Rab proteins ( 28,29 ), as well as fusion of LEs/Ls ( 38 ). NPC1 defi ciency is particularly detrimental for the functioning of LEs/Ls in the brain ( 39 ).…”

Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann–Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis*

“…4C). Mitochondrial dysfunction plays an important role in NPC pathogenesis (19). The perturbation of mitochondrial proteins can be associated with the observation that endosomal cholesterol is transported to the mitochondria in the absence of functional NPC1 leading to a buildup of cholesterol (19,23).…”

“…Mitochondrial dysfunction plays an important role in NPC pathogenesis (19). The perturbation of mitochondrial proteins can be associated with the observation that endosomal cholesterol is transported to the mitochondria in the absence of functional NPC1 leading to a buildup of cholesterol (19,23). Mitochondria are important for sterol metabolism and they harbor the cytochrome P450 side chain cleavage enzyme, which converts cholesterol into pregnenolone, the precursor of steroids (24).…”

Cholesterol Homeostasis Imbalance and Brain Functioning: Neurological Disorders and Behavioral Consequences

“…As far as is known, after LDL cholesteryl ester hydrolysis into lysosomes, NPC2 binds cholesterol. Subsequently, NPC2 transfers the sterol to NPC1, thus determining the exit of free cholesterol from lysosomes [65]. Approximately 95% of the patients express mutations in the NPC1 gene, whereas the remaining 5% display mutations in the NPC2 gene.…”