An in vitro model yields ‘importin’ new insights into chronic traumatic encephalopathy: damaged astrocytes stop ‘thrombospondin’ to the injury An Editorial Highlight for ‘Defective synthesis and release of astrocytic thrombospondin‐1 mediates the neuronal TDP‐43 proteinopathy, resulting in defects in neuronal integrity associated with chronic traumatic encephalopathy: in vitro studies’
JournalJournal of Neurochemistry
PublisherBlackwell Publishing Ltd
MetadataShow full item record
AbstractThis Editorial highlights a study by Jayakumar and colleagues (2016) in the current issue of Journal of Neurochemistry. The authors introduce an in vitro model of chronic traumatic encephalopathy (CTE) to explore the mechanistic underpinnings of CTE pathogenesis, including investigation of how traumatized astrocytes affect traumatized neurons through the release of secreted factors. The model recapitulates two key features of the human post-mortem CTE brain: neuronal tauopathy and TDP-43 proteinopathy—the respective accretion of hyperphosphorylated tau and cytoplasmic hyperphosphorylated and ubiquitinated TDP-43. Oxidative stress and casein kinase 1 episilon (CK1ε) are identified as key upstream regulators of cytoplasmic TDP-43 phosphorylation, and this phosphorylation is found to correlate with decreased importin-β protein level and a decline in synaptic integrity. RNA silencing of importin-β is sufficient to mimic both the phospho-TDP-43 accumulation and synaptic injury observed after mild in vitro trauma. Strikingly, Jayakumar et al. find that thrombospondin-1 (TSP-1), a protein secreted by traumatized astrocytes at elevated levels during the initial 5 days after damage, can attenuate CK1ε phosphorylation of TDP-43 and synaptic injury. However, TSP-1 secretion by astrocytes is lost at 10–15 days post-injury, and neurons succumb to unchecked TDP-43 pathogenesis.
SponsorsThe authors are supported by the National Institutes of Health (R01 NS085165 and R21 NS096538 grants to B.M.P.) and the M. Jane Matjasko Endowment (S.M.J.). The authors report no conflicts of interest.
Chronic Traumatic Encephalopathy
Casein Kinase Iepsilon
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85011844930&doi=10.1111%2fjnc.13906&partnerID=40&md5=be83209a42b38cd069ef68133dfa2170; http://hdl.handle.net/10713/10960