Reduced Translocation of Nascent Prion Protein During ER Stress Contributes to Neurodegeneration

• Published in: Developmental cell Vol. 15; no. 3; pp. 359 - 370
• Main Authors: Rane, Neena S., Kang, Sang-Wook, Chakrabarti, Oishee, Feigenbaum, Lionel, Hegde, Ramanujan S.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 01-09-2008; Cell Press
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Biological Transport - physiology; Brain - cytology; Brain - metabolism; Brain - pathology; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; CELLBIO; Cricetinae; Cricetulus; Endoplasmic Reticulum - metabolism; Fundamental and applied biological sciences. Psychology; HUMDISEASE; Mice; Mice, Transgenic; Microbiology; Molecular and cellular biology; Molecular Sequence Data; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Non conventional transmissible agents; Oxidative Stress; Prions - genetics; Prions - metabolism; Protein Sorting Signals - genetics; PROTEINS; PrPSc Proteins - genetics; PrPSc Proteins - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Scrapie - metabolism; CELLBIO; PROTEINS; HUMDISEASE; Translocation; Development; Degenerative disease; Prion; Protein; Stress
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2008.06.015

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.