Impaired proteolysis underlies autophagic dysfunction in Niemann-Pick type C disease

Matthew J. Elrick, Ting Yu, Chan Chung, Andrew P. Lieberman

Research output: Contribution to journalArticlepeer-review

95 Scopus citations


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.

Original languageEnglish (US)
Article numberdds324
Pages (from-to)4876-4887
Number of pages12
JournalHuman molecular genetics
Issue number22
StatePublished - Nov 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Impaired proteolysis underlies autophagic dysfunction in Niemann-Pick type C disease'. Together they form a unique fingerprint.

Cite this