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.

Keywords: :

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

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Disclosure of Potential Conflicts of Interest

RJ is an advisor to Stemgent and Fate Therapeutics.

Acknowledgments

We thank NNPD Foundation (DM) and BBSRC New Investigator Award (VIK) for funding and Tom DiCesare (BARC, Whitehead Institute) for help with illustrations. This work is supported by US NIH grants R37-CA084198 and R01-CA087869 (RJ). SS and VIK are also former fellows of Hughes Hall, University of Cambridge, UK.