Impaired autophagy in the lipid-storage disorder niemann-pick type c1 disease

Sovan Sarkar, Bernadette Carroll, Yosef Buganim, Dorothea Maetzel, Alex H.M. Ng, John P. Cassady, Malkiel A. Cohen, Souvik Chakraborty, Haoyi Wang, Eric Spooner, Hidde Ploegh, Joerg Gsponer, Viktor I. Korolchuk, Rudolf Jaenisch*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

149 Citations (Scopus)

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, mayprovide a rational treatment strategy for NPC1 disease.

Original languageEnglish
Pages (from-to)1302-1315
Number of pages14
JournalCell Reports
Volume5
Issue number5
DOIs
Publication statusPublished - 12 Dec 2013

Fingerprint

Dive into the research topics of 'Impaired autophagy in the lipid-storage disorder niemann-pick type c1 disease'. Together they form a unique fingerprint.

Cite this