Prion-mediated neurodegeneration is associated with early impairment of the ubiquitin–proteasome system

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• 作者：Chris McKinnon ; Rob Goold ; Ralph Andre ; Anny Devoy ; Zaira Ortega…
• 关键词：Prion ; PrP ; UPS ; Proteasome ; Neurodegeneration
• 刊名：Acta Neuropathologica
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：131
• 期：3
• 页码：411-425
• 全文大小：6,377 KB
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• 作者单位：Chris McKinnon (1)
  Rob Goold (1)
  Ralph Andre (1)
  Anny Devoy (1)
  Zaira Ortega (2) (3)
  Julie Moonga (1)
  Jacqueline M. Linehan (4)
  Sebastian Brandner (1) (5)
  José J. Lucas (2) (3)
  John Collinge (1) (4)
  Sarah J. Tabrizi (1)
  
  1. Department of Neurodegenerative Disease, University College London, Institute of Neurology, Queen Square, London, WC1N 3BG, UK
  2. Centro de Biología Molecular “Severo Ochoa”, (CBMSO) CSIC/UAM, Madrid, Spain
  3. Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
  4. MRC Prion Unit, University College London, Institute of Neurology, Queen Square, London, UK
  5. Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Pathology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0533

文摘

Prion diseases are a group of fatal neurodegenerative disorders characterised by the accumulation of misfolded prion protein (PrPSc) 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 UbG76V-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 PrPSc 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 PrPSc load. Taken together, these results identify the UPS as a possible early mediator of prion pathogenesis and promising target for development of future therapeutics. Keywords Prion PrP UPS Proteasome Neurodegeneration