title: Restarting stalled autophagy a potential therapeutic approach for the lipid storage disorder, Niemann-Pick type C1 disease.
abstract: Autophagy is essential for cellular homeostasis and its dysfunction in human diseases has been implicated in the accumulation of misfolded protein and in cellular toxicity. We have recently shown impairment in autophagic flux in the lipid storage disorder, Niemann-Pick type C1 (NPC1) disease associated with abnormal cholesterol sequestration, where maturation of autophagosomes is impaired due to defective amphisome formation caused by failure in SNARE machinery. Abrogation of autophagy also causes cholesterol accumulation, suggesting that defective autophagic flux in NPC1 disease may act as a primary causative factor not only by imparting its deleterious effects, but also by increasing cholesterol load. However, cholesterol depletion treatment with HP-β-cyclodextrin impedes autophagy, whereas pharmacologically stimulating autophagy restores its function independent of amphisome formation. Of potential therapeutic relevance is that a low dose of HP-β-cyclodextrin that does not perturb autophagy, coupled with an autophagy inducer, may rescue both the cholesterol and autophagy defects in NPC1 disease.
authors.affiliation: Whitehead Institute for Biomedical Research; Massachusetts Institute of Technology; Cambridge, MA USA.
authors.forename: Sovan
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Whitehead Institute for Biomedical Research; Massachusetts Institute of Technology; Cambridge, MA USA.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Maetzel
authors.affiliation: Institute for Ageing and Health; Newcastle University; Campus for Ageing and Vitality; Newcastle upon Tyne, UK.
authors.forename: Viktor I
authors.initials: VI
authors.lastname: Korolchuk
authors.affiliation: Whitehead Institute for Biomedical Research; Massachusetts Institute of Technology; Cambridge, MA USA; Skolkovo Institute of Science and Technology (Skoltech); Skolkovo, Moscow Region, Russia.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D050600:SNARE Proteins / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000627:therapeutic use*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D050505:Mutant Proteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D050600:SNARE Proteins; D047392:beta-Cyclodextrins; D002784:Cholesterol; C031215:betadex
keywords: Niemann-Pick disease; amphisome; autophagic flux; autophagy enhancer; cholesterol; lipid storage disorder; lysosomal storage disorder