Joy MT, Ben Assayag E, Shabashov-Stone D, Liraz-Zaltsman S, Mazzitelli J, Arenas M, Abduljawad N, Kliper E, Korczyn AD, Thareja NS, Kesner EL, Zhou M, Huang S, Silva TK, Katz N, Bornstein NM, Silva AJ, Shohami E, Carmichael ST. CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury. Cell. 2019 Feb 21;176(5):1143-1157.e13. PubMed.
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Icahn School of Medicine at Mount Sinai
The report on CCR5 provides prima facie evidence of the long-held notion that much of the damage to neurons in brain disease occurs not as a result of the primary event, but due to activation of signaling by cytokines and other transmitters. This dovetails well with the recent network computational analysis by Emilie Castranio and colleagues at the University of Pittsburgh, who studied brain post-TBI and discovered that the signaling network centered around the TYROBP/DAP12 hub (driver) was selectively perturbed (Castranio et al., 2017).
TYROBP/DAP12 is the transmembrane adaptor responsible for signaling across TREM2 and CR3 and passing signals along to Syk protein kinase. C1q seems to be essential in this process, as shown by Mickael Audrain, Jean-Vianney Haure-Mirande and their colleagues at the Icahn School of Medicine at Mount Sinai in their back-to-back papers in press in the early online electronic publication section of Molecular Psychiatry (Audrain et al. 2018; Haure-Mirande et al., 2018).
What is also impressive is the ability of neurons to express molecules previously considered to be strictly the purview of inflammatory and immune cells. This creates enormous complexity in attempting to predict which immune inflammatory molecules are most important at which stages and in which cells.
This new CCR5 paper is groundbreaking in that the benefit is already established, and now Joy et al. and others can focus on working backward to discover the molecular underpinnings.
References:
Castranio EL, Mounier A, Wolfe CM, Nam KN, Fitz NF, Letronne F, Schug J, Koldamova R, Lefterov I. Gene co-expression networks identify Trem2 and Tyrobp as major hubs in human APOE expressing mice following traumatic brain injury. Neurobiol Dis. 2017 Sep;105:1-14. Epub 2017 May 11 PubMed.
Audrain M, Haure-Mirande JV, Wang M, Kim SH, Fanutza T, Chakrabarty P, Fraser P, St George-Hyslop PH, Golde TE, Blitzer RD, Schadt EE, Zhang B, Ehrlich ME, Gandy S. Integrative approach to sporadic Alzheimer's disease: deficiency of TYROBP in a tauopathy mouse model reduces C1q and normalizes clinical phenotype while increasing spread and state of phosphorylation of tau. Mol Psychiatry. 2019 Sep;24(9):1383-1397. Epub 2018 Oct 3 PubMed.
Haure-Mirande JV, Wang M, Audrain M, Fanutza T, Kim SH, Heja S, Readhead B, Dudley JT, Blitzer RD, Schadt EE, Zhang B, Gandy S, Ehrlich ME. Correction: Integrative approach to sporadic Alzheimer's disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden. Mol Psychiatry. 2019 Mar;24(3):472. PubMed.
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