Niemann-Pick Disease Type C (NPDC) by Mutation of NPC1 and NPC2: Aberrant Lysosomal Cholesterol Trafficking and Oxidative Stress
Abstract
:1. Introduction
2. The Relationship between NPDC and Lysosomes
2.1. Lysosomal Appearance and the Changes in Lysosomes in NPDC
2.2. The Effect of the Lysosomal Proteins on NPDC
3. NPDC in Other Intracellular Organelles
4. Current Therapeutic Strategies for NPDC
4.1. Antioxidant-Related Drugs for NPDC Treatment
4.1.1. N-Butyl-Deoxynojirimycin (Miglustat)
4.1.2. N-Acetylcysteine and Coenzyme Q10
4.1.3. Heat Shock Factor
4.1.4. Cyclodextrin
4.2. Non-Antioxidant Methods for NPDC Treatment
4.2.1. Lysophagy
4.2.2. Histone Deacetylase Inhibitors
4.2.3. Adenovirus
5. Conclusions and Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Induction of NPDC | Organelle Appearance | Strain and Cell Types | Ref. | |
---|---|---|---|---|
Lysosome | NPC1 knock-out | Destruction of lysosomal morphology | NPDC mice platelets | [52] |
Increase in LAMP-1 | NPDC patients | [53,54] | ||
Hyperglycosylation of LAMP-1 | NPC1 knock-out mice | [55] | ||
U18666a | Decrease in lysosomal Ca2+ release | MEG-01 | [52] | |
RAW 264.7 | [58] | |||
Accumulation of Ptdlns4P and PI4K | NPDC patient fibroblasts | [61] | ||
Golgi | Mutation of NPC1 | Mis-localization of caveolin-1 | Mouse embryonic fibroblasts | [62] |
U18666a | Mis-localization of TGN marker syntaxin 6 | CHO cells | [63] | |
Accumulation of Ptdlns4P | Human embryonal kidney tsA201 cells | [64] | ||
Inhibition of OSBP secretion | NPDC fibroblasts | [65] | ||
Mitochondria | Knock-down of NPC1 | Cholesterol accumulation in mitochondria with oxidative stress | CHO cells | [66] |
Mutation of NPC1 | Decrease in mitochondrial volume | Purkinje cells | [67] | |
NPC2 deficiency | Decrease in mitochondrial respiration | 3T3-L1 adipocytes, hepatic stellate cells, and NPDC patient fibroblasts | [68,69,70] | |
U18666a | Decrease in ATP generation with apoptosis | Mice brains | [45,71] | |
ER | NPC1 mutation | Up-regulation of ER stress-related genes | CHO cells | [72] |
Disruption of IP3R | Human fibroblasts | [73] | ||
Knock-down of NPC1 | Inhibition of ER-lysosome fusion | CHO cells | [72] | |
U18666a | ||||
Lysosome | Knock-out of BORC and ARL8 | Accumulation of cholesterol in lysosomes | Hela cells | [74] |
Inhibition of mTORC1 by Torin1 | Recovery of mitochondrial damage and lysosomal membrane damage | NPC1 knock-out in mouse embryonic fibroblasts | [75] | |
Activation of TFEB by genistein | Increase in LC3 II expression | NPDC patient fibroblasts | [76] | |
Activation of TPC2 | Decrease in lysosomal cholesterol level by exocytosis | NPC1-mutated human fibroblasts | [77] | |
Golgi | Overexpression of rab7 and rab9 | Recovery of Golgi marker | Human skin fibroblasts | [78] |
Depletion of VPS53 | Inhibition of NPC2 recruitment | CHO cells | [79] | |
Mitochondria | Stimulation of TRAP1 | Activation of AMPK and inhibition of cholesterol trafficking from lysosomes to ER | Mouse NPDC cells | [80] |
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Lee, D.; Hong, J.H. Niemann-Pick Disease Type C (NPDC) by Mutation of NPC1 and NPC2: Aberrant Lysosomal Cholesterol Trafficking and Oxidative Stress. Antioxidants 2023, 12, 2021. https://doi.org/10.3390/antiox12122021
Lee D, Hong JH. Niemann-Pick Disease Type C (NPDC) by Mutation of NPC1 and NPC2: Aberrant Lysosomal Cholesterol Trafficking and Oxidative Stress. Antioxidants. 2023; 12(12):2021. https://doi.org/10.3390/antiox12122021
Chicago/Turabian StyleLee, Dongun, and Jeong Hee Hong. 2023. "Niemann-Pick Disease Type C (NPDC) by Mutation of NPC1 and NPC2: Aberrant Lysosomal Cholesterol Trafficking and Oxidative Stress" Antioxidants 12, no. 12: 2021. https://doi.org/10.3390/antiox12122021