Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol.
Changes in prion protein (PrP) folding are associated with fatal neurodegenerative disorders, but the neurotoxic species is unknown. Like other proteins that traffic through the endoplasmic reticulum, misfolded PrP is retrograde transported to the cytosol for degradation by proteasomes. Accumulation of even small amounts of cytosolic PrP was strongly neurotoxic in cultured cells and transgenic mice. Mice developed normally but acquired severe ataxia, with cerebellar degeneration and gliosis. This establishes a mechanism for converting wild-type PrP to a highly neurotoxic species that is distinct from the self-propagating PrP(Sc) isoform and suggests a potential common framework for seemingly diverse PrP neurodegenerative disorders.
Ma
Jiyan
J
Howard Hughes Medical Institute, Department of Pathology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Wollmann
Robert
R
Lindquist
Susan
S
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism*; D006031:Glycosylation; D020287:In Situ Nick-End Labeling; D007976:Leupeptins / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009410:Nerve Degeneration; D009474:Neurons / Q000502:physiology*; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism; D053764:Presenilin-1; D017096:Prion Diseases / Q000378:metabolism* / Q000473:pathology; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex; D011487:Protein Conformation; D017510:Protein Folding; D021381:Protein Transport; D014162:Transfection; D014407:Tumor Cells, Cultured
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D018620:PrPSc Proteins; D053764:Presenilin-1; D011328:Prions; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde