title: Prion-mediated neurodegeneration is associated with early impairment of the ubiquitin-proteasome system.
abstract: Prion diseases are a group of fatal neurodegenerative disorders characterised by the accumulation of misfolded prion protein (PrP(Sc)) in the brain. The critical relationship between aberrant protein misfolding and neurotoxicity currently remains unclear. The accumulation of aggregation-prone proteins has been linked to impairment of the ubiquitin-proteasome system (UPS) in a variety of neurodegenerative disorders, including Alzheimer's, Parkinson's and Huntington's diseases. As the principal route for protein degradation in mammalian cells, this could have profound detrimental effects on neuronal function and survival. Here, we determine the temporal onset of UPS dysfunction in prion-infected Ub(G76V)-GFP reporter mice, which express a ubiquitin fusion proteasome substrate to measure in vivo UPS activity. We show that the onset of UPS dysfunction correlates closely with PrP(Sc) deposition, preceding earliest behavioural deficits and neuronal loss. UPS impairment was accompanied by accumulation of polyubiquitinated substrates and found to affect both neuronal and astrocytic cell populations. In prion-infected CAD5 cells, we demonstrate that activation of the UPS by the small molecule inhibitor IU1 is sufficient to induce clearance of polyubiquitinated substrates and reduce misfolded PrP(Sc) load. Taken together, these results identify the UPS as a possible early mediator of prion pathogenesis and promising target for development of future therapeutics.
authors.affiliation: Department of Neurodegenerative Disease, University College London, Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: McKinnon
authors.affiliation: Department of Neurodegenerative Disease, University College London, Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Rob
authors.initials: R
authors.lastname: Goold
authors.affiliation: Department of Neurodegenerative Disease, University College London, Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Ralph
authors.initials: R
authors.lastname: Andre
authors.affiliation: Department of Neurodegenerative Disease, University College London, Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Anny
authors.initials: A
authors.lastname: Devoy
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", (CBMSO) CSIC/UAM, Madrid, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Zaira
authors.initials: Z
authors.lastname: Ortega
authors.affiliation: Department of Neurodegenerative Disease, University College London, Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Moonga
authors.affiliation: MRC Prion Unit, University College London, Institute of Neurology, Queen Square, London, UK.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Linehan
authors.affiliation: Department of Neurodegenerative Disease, University College London, Institute of Neurology, Queen Square, London, WC1N 3BG, UK.|Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", (CBMSO) CSIC/UAM, Madrid, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: José J
authors.initials: JJ
authors.lastname: Lucas
authors.affiliation: Department of Neurodegenerative Disease, University College London, Institute of Neurology, Queen Square, London, WC1N 3BG, UK.|MRC Prion Unit, University College London, Institute of Neurology, Queen Square, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.affiliation: Department of Neurodegenerative Disease, University College London, Institute of Neurology, Queen Square, London, WC1N 3BG, UK. s.tabrizi@prion.ucl.ac.uk.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D018620:PrPSc Proteins / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D018620:PrPSc Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: Neurodegeneration; PrP; Prion; Proteasome; UPS