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Using the C57BL\/6J mouse, a mouse strain that can be infected by the A\/Vietnam\/1203\/04 H5N1 virus without adaptation, we show that this virus travels from the peripheral nervous system into the CNS to higher levels of the neuroaxis. In regions infected by H5N1 virus, we observe activation of microglia and alpha-synuclein phosphorylation and aggregation that persists long after resolution of the infection. We also observe a significant loss of dopaminergic neurons in the substantia nigra pars compacta 60 days after infection. Our results suggest that a pandemic H5N1 pathogen, or other neurotropic influenza virus, could initiate CNS disorders of protein aggregation including Parkinson's and Alzheimer's diseases.<\/jats:p>","DOI":"10.1073\/pnas.0900096106","type":"journal-article","created":{"date-parts":[[2009,8,10]],"date-time":"2009-08-10T21:28:49Z","timestamp":1249939729000},"page":"14063-14068","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":417,"title":["Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration"],"prefix":"10.1073","volume":"106","author":[{"given":"Haeman","family":"Jang","sequence":"first","affiliation":[{"name":"Departments of aDevelopmental Neurobiology and"},{"name":"Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Boltz","sequence":"additional","affiliation":[{"name":"Infectious Diseases\/Virology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharine","family":"Sturm-Ramirez","sequence":"additional","affiliation":[{"name":"Infectious Diseases\/Virology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kennie R.","family":"Shepherd","sequence":"additional","affiliation":[{"name":"Departments of aDevelopmental Neurobiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Jiao","sequence":"additional","affiliation":[{"name":"Departments of aDevelopmental Neurobiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Webster","sequence":"additional","affiliation":[{"name":"Infectious Diseases\/Virology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Smeyne","sequence":"additional","affiliation":[{"name":"Departments of aDevelopmental Neurobiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,8,18]]},"reference":[{"key":"e_1_3_3_1_2","volume-title":"Cumulative Number of Confirmed Human Cases of Avian Influenza A\/(H5N1) Reported to WHO","year":"2008","unstructured":"Cumulative Number of Confirmed Human Cases of Avian Influenza A\/(H5N1) Reported to WHO (WHO, Geneva, 2008)."},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0306-9877(85)90034-9"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(82)90820-0"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1354\/vp.43-4-500"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa044307"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60627-3"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2003.08.005"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7742(07)82016-2"},{"key":"e_1_3_3_9_2","first-page":"80","article-title":"Qualitative and quantitative analysis of locus coeruleus neurons in Parkinson's disease","volume":"35","author":"Bertrand E","year":"1997","unstructured":"E Bertrand, W Lechowicz, GM Szpak, J Dymecki, Qualitative and quantitative analysis of locus coeruleus neurons in Parkinson's disease. 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