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To examine whether these proteins contribute to the development of CTE<\/jats:styled-content>, we utilized an in\u00a0vitro<\/jats:italic> trauma system known to reproduce many of the findings observed in humans and experimental animals with traumatic brain injury. Accordingly, we examined the role of TDP<\/jats:styled-content>\u201043 and Tau in an in\u00a0vitro<\/jats:italic> model of trauma, and determined whether these proteins contribute to the defective neuronal integrity associated with CNS<\/jats:styled-content> trauma. Single or multiple episodes of trauma to cultured neurons resulted in a time\u2010dependent increase in cytosolic levels of phosphorylated TDP<\/jats:styled-content>\u201043 (p\u2010TDP<\/jats:styled-content>\u201043). Trauma to cultured neurons also caused an increase in levels of casein kinase 1 epsilon (CK<\/jats:styled-content>1\u03b5), and ubiquitinated p\u2010TDP<\/jats:styled-content>\u201043, along with a decrease in importin\u2010\u03b2 (all factors known to mediate the \u201cTDP<\/jats:styled-content>\u201043 proteinopathy\u201d). Defective neuronal integrity, as evidenced by a reduction in levels of the NR<\/jats:styled-content>1 subunit of the NMDA<\/jats:styled-content> receptor, and in PSD<\/jats:styled-content>95, along with increased levels of phosphorylated tau were also observed. Additionally, increased levels of intra\u2010 and extracellular thrombospondin\u20101 (TSP<\/jats:styled-content>\u20101) (a factor known to regulate neuronal integrity) were observed in cultured astrocytes at early stages of trauma, while at later stages decreased levels were identified. The addition of recombinant TSP<\/jats:styled-content>\u20101, conditioned media from cultured astrocytes at early stages of trauma, or the CK<\/jats:styled-content>1\u03b5 inhibitor PF<\/jats:styled-content>4800567 hydrochloride to traumatized cultured neurons reduced levels of p\u2010TDP<\/jats:styled-content>\u201043, and reversed the trauma\u2010induced decline in NR<\/jats:styled-content>1 subunit of the NMDA<\/jats:styled-content> receptor and PSD<\/jats:styled-content>95 levels. These findings suggest that a trauma\u2010induced increase in TDP<\/jats:styled-content>\u201043 phosphorylation contributes to defective neuronal integrity, and that increasing TSP<\/jats:styled-content>\u20101 levels may represent a useful therapeutic approach for the prevention of the neuronal TDP<\/jats:styled-content>\u201043 proteinopathy associated with CTE<\/jats:styled-content>.<\/jats:p><\/jats:sec>\nimage<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p>Read the Editorial Highlight for this article on page 531<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13867","type":"journal-article","created":{"date-parts":[[2016,10,14]],"date-time":"2016-10-14T02:37:45Z","timestamp":1476412665000},"page":"645-661","source":"Crossref","is-referenced-by-count":21,"title":["Defective synthesis and release of astrocytic thrombospondin\u20101 mediates the neuronal TDP<\/scp>\u201043 proteinopathy, resulting in defects in neuronal integrity associated with chronic traumatic encephalopathy: in\u00a0vitro<\/i> studies"],"prefix":"10.1111","volume":"140","author":[{"given":"Arumugam Radhakrishnan","family":"Jayakumar","sequence":"first","affiliation":[{"name":"Laboratory of Neuropathology Veterans Affairs Medical Center Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao Y.","family":"Tong","sequence":"additional","affiliation":[{"name":"Departments of Pathology University of Miami School of Medicine Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagarajarao","family":"Shamaladevi","sequence":"additional","affiliation":[{"name":"Urology University of Miami School of Medicine Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Barcelona","sequence":"additional","affiliation":[{"name":"Departments of Pathology University of Miami School of Medicine Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Gaidosh","sequence":"additional","affiliation":[{"name":"Ophthalmology University of Miami School of Medicine Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apeksha","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Departments of Pathology University of Miami School of Medicine Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Norenberg","sequence":"additional","affiliation":[{"name":"Laboratory of Neuropathology Veterans Affairs Medical Center Miami Florida USA"},{"name":"Departments of Pathology University of Miami School of Medicine Miami Florida USA"},{"name":"Biochemistry & Molecular Biology University of Miami School of Medicine Miami Florida USA"},{"name":"Neurology University of Miami School of Medicine Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,1,10]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0049279"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1789.2009.01089.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-011-0850-y"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.3171\/2016.2.FOCUS15609"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4988-09.2010"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00955101"},{"key":"e_1_2_7_8_1","first-page":"783","article-title":"Immunohistochemical identification of thrombospondin in normal human brain and in Alzheimer's disease","volume":"141","author":"Bu\u00e8e L.","year":"1992","journal-title":"Am. 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