title: Neurotoxic effects of the HCV core protein are mediated by sustained activation of ERK via TLR2 signaling.
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.
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093-0624, USA.
authors.forename: Amy D
authors.initials: AD
authors.lastname: Paulino
authors.forename: Kiren
authors.initials: K
authors.lastname: Ubhi
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Leslie
authors.initials: L
authors.lastname: Crews
authors.forename: Scott
authors.initials: S
authors.lastname: Letendre
authors.forename: Ronald
authors.initials: R
authors.lastname: Ellis
authors.forename: Ian P
authors.initials: IP
authors.lastname: Everall
authors.forename: Igor
authors.initials: I
authors.lastname: Grant
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D060085:Coinfection; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D006678:HIV / Q000502:physiology; D015658:HIV Infections / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016174:Hepacivirus / Q000472:pathogenicity / Q000502:physiology; D006526:Hepatitis C / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D006624:Hippocampus / Q000473:pathology / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D007267:Injections; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D014758:Viral Core Proteins / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051195:Toll-Like Receptor 2; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D020930:MAP Kinase Kinase Kinases