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Autophagy. 2014 Jun;10(6):1137-40. doi: 10.4161/auto.28623.

Restarting stalled autophagy a potential therapeutic approach for the lipid storage disorder, Niemann-Pick type C1 disease.

Author information

1
Whitehead Institute for Biomedical Research; Massachusetts Institute of Technology; Cambridge, MA USA.
2
Institute for Ageing and Health; Newcastle University; Campus for Ageing and Vitality; Newcastle upon Tyne, UK.
3
Whitehead Institute for Biomedical Research; Massachusetts Institute of Technology; Cambridge, MA USA; Skolkovo Institute of Science and Technology (Skoltech); Skolkovo, Moscow Region, Russia.

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.

KEYWORDS:

Niemann-Pick disease; amphisome; autophagic flux; autophagy enhancer; cholesterol; lipid storage disorder; lysosomal storage disorder

PMID:
24879158
PMCID:
PMC4091173
DOI:
10.4161/auto.28623
[Indexed for MEDLINE]
Free PMC Article

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