PMID- 27585976 OWN - NLM STAT- MEDLINE DCOM- 20171024 LR - 20231213 IS - 2051-5960 (Electronic) IS - 2051-5960 (Linking) VI - 4 IP - 1 DP - 2016 Sep 1 TI - Systemic inflammation disrupts oligodendrocyte gap junctions and induces ER stress in a model of CNS manifestations of X-linked Charcot-Marie-Tooth disease. PG - 95 LID - 10.1186/s40478-016-0369-5 [doi] LID - 95 AB - X-linked Charcot-Marie-Tooth disease (CMT1X) is a common form of inherited neuropathy resulting from different mutations affecting the gap junction (GJ) protein connexin32 (Cx32). A subset of CMT1X patients may additionally present with acute fulminant CNS dysfunction, typically triggered by conditions of systemic inflammation and metabolic stress. To clarify the underlying mechanisms of CNS phenotypes in CMT1X we studied a mouse model of systemic inflammation induced by lipopolysaccharide (LPS) injection to compare wild type (WT), connexin32 (Cx32) knockout (KO), and KO T55I mice expressing the T55I Cx32 mutation associated with CNS phenotypes. Following a single intraperitoneal LPS or saline (controls) injection at the age of 40-60 days systemic inflammatory response was documented by elevated TNF-alpha and IL-6 levels in peripheral blood and mice were evaluated 1 week after injection. Behavioral analysis showed graded impairment of motor performance in LPS treated mice, worse in KO T55I than in Cx32 KO and in Cx32 KO worse than WT. Iba1 immunostaining revealed widespread inflammation in LPS treated mice with diffusely activated microglia throughout the CNS. Immunostaining for the remaining major oligodendrocyte connexin Cx47 and for its astrocytic partner Cx43 revealed widely reduced expression of Cx43 and loss of Cx47 GJs in oligodendrocytes. Real-time PCR and immunoblot analysis indicated primarily a down regulation of Cx43 expression with secondary loss of Cx47 membrane localization. Inflammatory changes and connexin alterations were most severe in the KO T55I group. To examine why the presence of the T55I mutant exacerbates pathology even more than in Cx32 KO mice, we analyzed the expression of ER-stress markers BiP, Fas and CHOP by immunostaining, immunoblot and Real-time PCR. All markers were increased in LPS treated KO T55I mice more than in other genotypes. In conclusion, LPS induced neuroinflammation causes disruption of the main astrocyte-oligodendrocyte GJs, which may contribute to the increased sensitivity of Cx32 KO mice to LPS and of patients with CMT1X to various stressors. Moreover the presence of an intracellularly retained, misfolded CMT1X mutant such as T55I induces ER stress under inflammatory conditions, further exacerbating oligodendrocyte dysfunction and pathological changes in the CNS. FAU - Olympiou, Margarita AU - Olympiou M AD - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus. FAU - Sargiannidou, Irene AU - Sargiannidou I AD - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus. FAU - Markoullis, Kyriaki AU - Markoullis K AD - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus. FAU - Karaiskos, Christos AU - Karaiskos C AD - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus. FAU - Kagiava, Alexia AU - Kagiava A AD - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus. FAU - Kyriakoudi, Styliana AU - Kyriakoudi S AD - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus. FAU - Abrams, Charles K AU - Abrams CK AD - Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, USA. FAU - Kleopa, Kleopas A AU - Kleopa KA AD - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus. kleopa@cing.ac.cy. AD - Neurology Clinics, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, 6 International Airport Avenue, P.O. Box 23462, , 1683, Nicosia, Cyprus. kleopa@cing.ac.cy. LA - eng PT - Journal Article DEP - 20160901 PL - England TA - Acta Neuropathol Commun JT - Acta neuropathologica communications JID - 101610673 RN - 0 (Aif1 protein, mouse) RN - 0 (Calcium-Binding Proteins) RN - 0 (Connexin 43) RN - 0 (Connexins) RN - 0 (GJA1 protein, mouse) RN - 0 (Interleukin-6) RN - 0 (Lipopolysaccharides) RN - 0 (Microfilament Proteins) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (connexin 47) RN - 0 (interleukin-6, mouse) SB - IM MH - Animals MH - Astrocytes/immunology/pathology MH - Calcium-Binding Proteins/metabolism MH - Charcot-Marie-Tooth Disease/*immunology/pathology MH - Connexin 43/metabolism MH - Connexins/genetics/metabolism MH - Disease Models, Animal MH - Endoplasmic Reticulum/*immunology/pathology MH - Endoplasmic Reticulum Stress/*physiology MH - Escherichia coli MH - Gap Junctions/*immunology/pathology MH - Inflammation/*immunology/pathology MH - Interleukin-6/blood MH - Lipopolysaccharides MH - Male MH - Mice, Knockout MH - Microfilament Proteins/metabolism MH - Neuroimmunomodulation/physiology MH - Oligodendroglia/*immunology/pathology MH - Tumor Necrosis Factor-alpha/blood MH - Gap Junction beta-1 Protein PMC - PMC5009701 OTO - NOTNLM OT - CMT1X OT - Cx43 OT - Cx47 OT - Gap junctions OT - LPS model OT - Oligodendrocytes EDAT- 2016/09/03 06:00 MHDA- 2017/10/25 06:00 PMCR- 2016/09/01 CRDT- 2016/09/03 06:00 PHST- 2016/08/16 00:00 [received] PHST- 2016/08/17 00:00 [accepted] PHST- 2016/09/03 06:00 [entrez] PHST- 2016/09/03 06:00 [pubmed] PHST- 2017/10/25 06:00 [medline] PHST- 2016/09/01 00:00 [pmc-release] AID - 10.1186/s40478-016-0369-5 [pii] AID - 369 [pii] AID - 10.1186/s40478-016-0369-5 [doi] PST - epublish SO - Acta Neuropathol Commun. 2016 Sep 1;4(1):95. doi: 10.1186/s40478-016-0369-5.