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An unresolved issue about many neurodegenerative diseases is why neurons are particularly sensitive to defects in ubiquitous cellular processes. One example is Niemann Pick type C1, caused by defects in cholesterol trafficking in all cells, but where neurons are preferentially damaged. Understanding this selective failure is limited by the difficulty in obtaining live human neurons from affected patients. To solve this problem, we generated neurons with decreased function of NPC1 from human embryonic stem cells and used them to test the hypothesis that defective cholesterol handling leads to enhanced pathological phenotypes in neurons. We found that human NPC1 neurons have strong spontaneous activation of autophagy, and, contrary to previous reports in patient fibroblasts, a block of autophagic progression leading to defective mitochondrial clearance. Mitochondrial fragmentation is an exceptionally severe phenotype in NPC1 neurons compared with fibroblasts, causing abnormal accumulation of mitochondrial proteins. Contrary to expectation, these abnormal phenotypes were rescued by treatment with the autophagy inhibitor 3-methyladenine and by treatment with the potential therapeutic cyclodextrin, which mobilizes cholesterol from the lysosomal compartment. Our findings suggest that neurons are especially sensitive to lysosomal cholesterol accumulation because of autophagy disruption and accumulation of fragmented mitochondria, thus defining a new route to effective drug development for NPC1 disease.
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http://dx.doi.org/10.1093/hmg/dds090 | DOI Listing |
Arch Dermatol Res
December 2024
Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shannxi, China.
Lipid metabolism disorders are frequently noted in atopic dermatitis (AD) patients, prompting the long-term use of lipid-lowering drugs. However, the causal effects of circulating lipids and different lipid-lowering drugs on the risk of AD are not thoroughly understood. Using publicly available genome-wide association studies (GWAS) summary data from two different cohorts, a series of Mendelian randomization (MR) analyses were conducted to explore the causal effects of genetically proxied circulating lipids and lipid-lowering drugs on the risk of AD.
View Article and Find Full Text PDFJ Neurosci Res
December 2024
National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Niemann Pick type C1 (NPC1) is a rare, fatal disorder characterized by endosomal lipid accumulation that leads to damage of both peripheral organs and central nervous system (cerebellum and hippocampus are especially affected). Currently, miglustat is the only approved drug for NPC1, thus the identification of new treatments is mandatory. We have previously demonstrated that the drug dipyridamole (DIP), an enhancer of adenosine signaling, can reduce the pathological phenotype in patient-derived fibroblasts.
View Article and Find Full Text PDFInt J Biol Macromol
December 2024
The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China. Electronic address:
The lipid-lowering activity of fucoidan has been widely reported, but the exploration of its mechanisms is relatively limited, and studies on its direct targets are even scarcer. Additionally, it is unclear whether different administration methods affect the lipid-lowering activity of fucoidan. In current study, we used fucoidan derived from Saccharina japonica (SJF) to investigate its targets.
View Article and Find Full Text PDFDrugs
December 2024
Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
Arimoclomol (MIPLYFFA™), an oral small molecule that crosses the blood brain barrier and is thought to upregulate CLEAR (Coordinated Lysosomal Expression and Regulation) network genes and improve lysosomal function, is being developed by Zevra Therapeutics Inc., for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC). In September 2024, arimoclomol was approved for use in combination with miglustat for the treatment of neurological manifestations of NPC in adult and pediatric patients 2 years of age and older in the USA.
View Article and Find Full Text PDFCell Biosci
December 2024
Division of Neuroscience, Dept. of Psychology, University La Sapienza, Via dei Sardi 70, 00185, Rome, Italy.
Background: The Niemann Pick C1 (NPC1) protein is an intracellular cholesterol transporter located in the late endosome/lysosome (LE/Ly) that is involved in the mobilization of endocytosed cholesterol. Loss-of-function mutations in the NPC1 gene lead to the accumulation of cholesterol and sphingolipids in LE/Ly, resulting in severe fatal NPC1 disease. Cellular alterations associated with NPC1 inactivation affect both the integrity of lipid rafts and the endocytic pathway.
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