RRC ID 67460
著者 Elrick MJ, Yu T, Chung C, Lieberman AP.
タイトル Impaired proteolysis underlies autophagic dysfunction in Niemann-Pick type C disease.
ジャーナル Hum Mol Genet
Abstract Niemann-Pick type C disease (NPC) is a childhood onset neurodegenerative disorder arising from lipid-trafficking defects caused by mutations in the NPC1 or NPC2 gene. Marked accumulation of autophagosomes is a prominent feature of NPC cells, yet a detailed understanding of the disease-associated alterations in autophagy and their role in pathogenesis has been lacking. Prior studies have shown that lipid storage in NPC disease induces autophagy. Here, we additionally show that the clearance of autophagosomes in NPC1 deficiency is impaired due to inhibition of lysosomal protease activity by stored lipids. We also demonstrate that the autophagic pathway is a source of stored cholesterol in the NPC lysosome, thus creating a positive feedback loop wherein autophagy induction exacerbates the disease via increased lipid storage. Inhibition of autophagy reduces cholesterol storage and restores normal lysosomal proteolysis in NPC1-deficient cells, supporting a model in which activation of the autophagic pathway promotes disease pathogenesis.
巻・号 21(22)
ページ 4876-87
公開日 2012-11-15
DOI 10.1093/hmg/dds324
PII dds324
PMID 22872701
PMC PMC3607480
MeSH Adaptor Proteins, Signal Transducing / metabolism Animals Autophagy* Carrier Proteins Cathepsins / metabolism Cell Line Cholesterol / metabolism Humans Intracellular Signaling Peptides and Proteins Lysosomes / metabolism Membrane Glycoproteins / deficiency Mice Mice, Knockout Models, Biological Neurons / metabolism Niemann-Pick C1 Protein Niemann-Pick Disease, Type C / genetics Niemann-Pick Disease, Type C / metabolism* Proteolysis* Sequestosome-1 Protein
IF 5.101
リソース情報
ヒト・動物細胞 Atg5^(+/+)MEF(RCB2710) Atg5^(-/-)MEF(RCB2711)