title: Reduced translocation of nascent prion protein during ER stress contributes to neurodegeneration.
abstract: During acute stress in the endoplasmic reticulum (ER), mammalian prion protein (PrP) is temporarily prevented from translocation into the ER and instead routed directly for cytosolic degradation. This "pre-emptive" quality control (pQC) system benefits cells by minimizing PrP aggregation in the secretory pathway during ER stress. However, the potential toxicity of cytosolic PrP raised the possibility that persistent pQC of PrP contributes to neurodegeneration in prion diseases. Here, we find evidence of ER stress and decreased translocation of nascent PrP during prion infection. Transgenic mice expressing a PrP variant with reduced translocation at levels expected during ER stress was sufficient to cause several mild age-dependent clinical and histological manifestations of PrP-mediated neurodegeneration. Thus, an ordinarily adaptive quality-control pathway can be contextually detrimental over long time periods. We propose that one mechanism of prion-mediated neurodegeneration involves an indirect ER stress-dependent effect on nascent PrP biosynthesis and metabolism.
authors.affiliation: Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Neena S
authors.initials: NS
authors.lastname: Rane
authors.affiliation: Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.affiliation: Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Oishee
authors.initials: O
authors.lastname: Chakrabarti
authors.affiliation: Laboratory of Animal Sciences, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.affiliation: Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA. Electronic address: hegder@mail.nih.gov.
authors.forename: Ramanujan S
authors.initials: RS
authors.lastname: Hegde
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D021382:Protein Sorting Signals / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012608:Scrapie / Q000378:metabolism
chemical_list: D018620:PrPSc Proteins; D011328:Prions; D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins