Article

Journal of NeuroVirology

, Volume 17, Issue 4, pp 327-340

Neurotoxic effects of the HCV core protein are mediated by sustained activation of ERK via TLR2 signaling

  • Amy D. PaulinoAffiliated withDepartment of Neurosciences, University of California San DiegoNeuropore Therapies Inc.
  • , Kiren UbhiAffiliated withDepartment of Neurosciences, University of California San Diego
  • , Edward RockensteinAffiliated withDepartment of Neurosciences, University of California San Diego
  • , Anthony AdameAffiliated withDepartment of Neurosciences, University of California San Diego
  • , Leslie CrewsAffiliated withDepartment of Pathology, University of California San Diego
  • , Scott LetendreAffiliated withDepartment of Medicine, University of California San Diego
  • , Ronald EllisAffiliated withDepartment of Neurosciences, University of California San Diego
  • , Ian P. EverallAffiliated withDepartment of Psychiatry and the HIV Neurobehavioral Research Center, University of California San DiegoDepartment of Psychiatry, University of Melbourne, Level 1 North, Royal Melbourne Hospital
  • , Igor GrantAffiliated withDepartment of Psychiatry and the HIV Neurobehavioral Research Center, University of California San DiegoVeterans Affairs Healthcare System
    • , Eliezer MasliahAffiliated withDepartment of Neurosciences, University of California San DiegoDepartment of Pathology, University of California San Diego Email author 

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Abstract

Hepatitis C virus (HCV) infection is a serious problem among those co-infected with human immunodeficiency virus; however, its impact in the central nervous system (CNS) remains unclear. This study aimed to investigate the mechanisms underlying HCV core protein-mediated neurodegeneration. Analysis of human HCV seropositive cases demonstrated widespread damage to neuronal dendritic processes and sustained activation of extracellular signal-related kinase (ERK); analogous pathologies were observed in wild type injected with HCV core protein into the hippocampus. In vitro analysis in neuronal cells exposed to HCV core demonstrated retraction of the neuronal processes in an ERK/Signal Transducer and Activator of Transcription 3 (STAT3)-dependent manner dependent on toll-like receptor 2 (TLR2) signaling activation. These results indicate that HCV core protein neurotoxicity may be mediated by the sustained activation of ERK/STAT3 via TLR2-IRAK1 signaling pathway. These pathways provide novel targets for development of neuroprotective treatments for HCV involvement of the CNS.

Keywords

HCV TLR2 Neurodegeneration ERK