title: Impaired autophagy in the lipid-storage disorder Niemann-Pick type C1 disease.
abstract: Autophagy dysfunction has been implicated in misfolded protein accumulation and cellular toxicity in several diseases. Whether alterations in autophagy also contribute to the pathology of lipid-storage disorders is not clear. Here, we show defective autophagy in Niemann-Pick type C1 (NPC1) disease associated with cholesterol accumulation, where the maturation of autophagosomes is impaired because of defective amphisome formation caused by failure in SNARE machinery, whereas the lysosomal proteolytic function remains unaffected. Expression of functional NPC1 protein rescues this defect. Inhibition of autophagy also causes cholesterol accumulation. Compromised autophagy was seen in disease-affected organs of Npc1 mutant mice. Of potential therapeutic relevance is that HP-β-cyclodextrin, which is used for cholesterol-depletion treatment, impedes autophagy, whereas stimulating autophagy restores its function independent of amphisome formation. Our data suggest that a low dose of HP-β-cyclodextrin that does not perturb autophagy, coupled with an autophagy inducer, may provide a rational treatment strategy for NPC1 disease.
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Sovan
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Carroll
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Buganim
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Maetzel
authors.affiliation: Department of Biochemistry and Molecular Biology, Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Alex H M
authors.initials: AH
authors.lastname: Ng
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Cassady
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Malkiel A
authors.initials: MA
authors.lastname: Cohen
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA.
authors.forename: Souvik
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Haoyi
authors.initials: H
authors.lastname: Wang
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Spooner
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Hidde
authors.initials: H
authors.lastname: Ploegh
authors.affiliation: Department of Biochemistry and Molecular Biology, Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Joerg
authors.initials: J
authors.lastname: Gsponer
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK.
authors.forename: Viktor I
authors.initials: VI
authors.lastname: Korolchuk
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA. Electronic address: jaenisch@wi.mit.edu.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
mesh_terms: D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D002784:Cholesterol / Q000172:deficiency / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D050600:SNARE Proteins / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D008562:Membrane Glycoproteins; C573152:NPC1 protein, rat; D000077296:Niemann-Pick C1 Protein; D050600:SNARE Proteins; D047392:beta-Cyclodextrins; D002784:Cholesterol