Format

Send to

Choose Destination
See comment in PubMed Commons below
Int J Cell Biol. 2013;2013:560421. doi: 10.1155/2013/560421. Epub 2013 Dec 17.

Early Delivery of Misfolded PrP from ER to Lysosomes by Autophagy.

Author information

  • 1Departments of Neurology, MC2030, The University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
  • 2Departments of Neurobiology, The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA.

Abstract

Prion diseases are linked to the accumulation of a misfolded isoform (PrP(Sc)) of prion protein (PrP). Evidence suggests that lysosomes are degradation endpoints and sites of the accumulation of PrP(Sc). We questioned whether lysosomes participate in the early quality control of newly generated misfolded PrP. We found PrP carrying the disease-associated T182A mutation (Mut-PrP) was delivered to lysosomes in a Golgi-independent manner. Time-lapse live cell imaging revealed early formation and uptake of GFP-tagged Mut-PrP aggregates into LysoTracker labeled vesicles. Compared with Wt-PrP, Mut-PrP expression was associated with an elevation in several markers of the autophagy-lysosomal pathway, and it extensively colocalized with the autophagosome-specific marker, LC3B. In autophagy deficient (ATG5(-/-)) mouse embryonic fibroblasts, or in normal cells treated with the autophagy-inhibitor 3-MA, Mut-PrP colocalization with lysosomes was reduced to a similar extent. Additionally, 3-MA selectively impaired the degradation of insoluble Mut-PrP, resulting in an increase in protease-resistant PrP, whereas the induction of autophagy by rapamycin reduced it. These findings suggest that autophagy might function as a quality control mechanism to limit the accumulation of misfolded PrP that normally leads to the generation of PrP(Sc).

PMID:
24454378
PMCID:
PMC3877647
DOI:
10.1155/2013/560421
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Hindawi Publishing Corporation Icon for PubMed Central
    Loading ...
    Support Center