piperidines and Niemann-Pick-Disease--Type-C

Most cells acquire cholesterol by endocytosis of circulating low-density lipoproteins (LDLs). After cholesteryl ester de-esterification in endosomes, free cholesterol is redistributed to intracellular membranes via unclear mechanisms. Our previous work suggested that the unconventional phospholipid lysobisphosphatidic acid (LBPA) may play a role in modulating the cholesterol flux through endosomes. In this study, we used the Prestwick library of FDA-approved compounds in a high-content, image-based screen of the endosomal lipids, lysobisphosphatidic acid and LDL-derived cholesterol. We report that thioperamide maleate, an inverse agonist of the histamine H3 receptor HRH3, increases highly selectively the levels of lysobisphosphatidic acid, without affecting any endosomal protein or function that we tested. Our data also show that thioperamide significantly reduces the endosome cholesterol overload in fibroblasts from patients with the cholesterol storage disorder Niemann-Pick type C (NPC), as well as in liver of Npc1

Topics: Animals; Cells, Cultured; Cholesterol; Endosomes; Female; Fibroblasts; HeLa Cells; Humans; Lysophospholipids; Male; Mice; Mice, Inbred BALB C; Monoglycerides; Niemann-Pick Disease, Type C; Piperidines

Neurodegenerative processes are often accompanied by disruption of cholinergic systems; therefore, acetylcholinesterase (AChE) inhibitors (AChEIs) may have therapeutic potential in some neurological conditions. We evaluated the effects of administration of donepezil, a widely used AChEI, in the cerebellum in a murine model of Niemann-Pick disease type C (NPC). The NPC mice developed Purkinje cell loss at the age of 8 weeks; 4-week-old NPC mice given donepezil led to improvement of Purkinje cell survival that was associated with improvement of motor dysfunction in the mice. Because abnormal accumulation of cholesterol caused by impaired lipid homeostasis is the principal pathogenetic mechanism underlying NPC, we investigated the effects of donepezil on cholesterol metabolism in the NPC mice. Donepezil treatment reduced cholesterol accumulation in adult neural stem cells in vitro, and it downregulated the expression of the cholesterol synthesis factors' sterol regulatory element-binding proteins and 3-hydroxy-3-methylglutaryl-CoA reductase in the cerebellum, implying that AChE activity might be associated with cholesterol homeostasis. Taken together, our findings suggest the role of a cholinergic pathway as a novel regulator of NPC progression and the potential application of AChEIs for the treatment of human NPC.

Topics: Adult Stem Cells; Animals; ATP-Binding Cassette Transporters; Cell Survival; Cells, Cultured; Cerebellum; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Gene Expression Regulation; Humans; Indans; Intracellular Signaling Peptides and Proteins; Lateral Ventricles; Liver X Receptors; Mice; Mice, Inbred BALB C; Mice, Transgenic; Movement Disorders; Mutation; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Orphan Nuclear Receptors; Piperidines; Proteins; Psychomotor Performance; Purkinje Cells; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Protein 2