Dataset Information

Tropomyosin Receptor Kinase B Expressed in Oligodendrocyte Lineage Cells Functions to Promote Myelin Following a Demyelinating Lesion.

ABSTRACT: The levels of brain-derived neurotrophic factor (BDNF) in the corpus callosum have previously been shown to have a critical impact on oligodendrocyte (OLG) lineage cells during cuprizone-elicited demyelination. In particular, BDNF+/- mice exhibit greater losses in myelin protein levels compared to wild-type mice after cuprizone. To investigate whether OLGs may directly mediate these effects of BDNF during a lesion in vivo, we used the cuprizone model of demyelination with inducible conditional male knockout mice to specifically delete the high-affinity tropomyosin receptor kinase B (TrkB) receptor from proteolipid protein?+?OLGs during cuprizone-elicited demyelination and subsequent remyelination. The loss of TrkB during cuprizone-elicited demyelination results in an increased sensitivity to demyelination as demonstrated by greater deficits in myelin protein levels, greater decreases in numbers of mature OLGs, increased numbers of demyelinated axons, and decreased myelin thickness. When mice are removed from cuprizone, they exhibit a delayed recovery in myelin proteins and myelin. Our data indicate that following a demyelinating lesion, TrkB in OLGs positively regulates myelin protein expression, myelin itself, and remyelination.

SUBMITTER: Huang Y

PROVIDER: S-EPMC7495938 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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Tropomyosin Receptor Kinase B Expressed in Oligodendrocyte Lineage Cells Functions to Promote Myelin Following a Demyelinating Lesion.

Huang Yangyang Y Song Yeri J YJ Isaac Maria M Miretzky Shir S Patel Ashish A Geoffrey McAuliffe W W Dreyfus Cheryl F CF

ASN neuro 20200101

The levels of brain-derived neurotrophic factor (BDNF) in the corpus callosum have previously been shown to have a critical impact on oligodendrocyte (OLG) lineage cells during cuprizone-elicited demyelination. In particular, BDNF+/- mice exhibit greater losses in myelin protein levels compared to wild-type mice after cuprizone. To investigate whether OLGs may directly mediate these effects of BDNF during a lesion <i>in vivo</i>, we used the cuprizone model of demyelination with inducible condit ...[more]

PMID: 32927995

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Project description:Myelin oligodendrocyte glycoprotein (MOG), a member of the immunoglobulin (Ig) superfamily, is a myelin protein solely expressed at the outermost surface of myelin sheaths and oligodendrocyte membranes. This makes MOG a potential target of cellular and humoral immune responses in inflammatory demyelinating diseases. Due to its late postnatal developmental expression, MOG is an important marker for oligodendrocyte maturation. Discovered about 30 years ago, it is one of the best-studied autoantigens for experimental autoimmune models for multiple sclerosis (MS). Human studies, however, have yielded controversial results on the role of MOG, especially MOG antibodies (Abs), as a biomarker in MS. But with improved detection methods using different expression systems to detect Abs in patients' samples, this is meanwhile no longer the case. Using cell-based assays with recombinant full-length, conformationally intact MOG, several recent studies have revealed that MOG Abs can be found in a subset of predominantly pediatric patients with acute disseminated encephalomyelitis (ADEM), aquaporin-4 (AQP4) seronegative neuromyelitis optica spectrum disorders (NMOSD), monophasic or recurrent isolated optic neuritis (ON), or transverse myelitis, in atypical MS and in N-methyl-d-aspartate receptor-encephalitis with overlapping demyelinating syndromes. Whereas MOG Abs are only transiently observed in monophasic diseases such as ADEM and their decline is associated with a favorable outcome, they are persistent in multiphasic ADEM, NMOSD, recurrent ON, or myelitis. Due to distinct clinical features within these diseases it is controversially disputed to classify MOG Ab-positive cases as a new disease entity. Neuropathologically, the presence of MOG Abs is characterized by MS-typical demyelination and oligodendrocyte pathology associated with Abs and complement. However, it remains unclear whether MOG Abs are a mere inflammatory bystander effect or truly pathogenetic. This article provides deeper insight into recent developments, the clinical relevance of MOG Abs and their role in the immunpathogenesis of inflammatory demyelinating disorders.

Project description:ImportanceIdentifying the course of demyelinating disease associated with myelin oligodendrocyte glycoprotein (MOG) autoantibodies is critical to guide appropriate treatment choices.ObjectiveTo characterize serial anti-MOG antibody serologies and clinical and imaging features at presentation and during follow-up in an inception cohort of prospectively monitored children with acquired demyelination.Design, setting, and participantsIn this prospective cohort study, study participants were recruited from July 2004 to February 2017 through the multicenter Canadian Pediatric Demyelinating Disease Study. Inclusion criteria included (1) incident central nervous system demyelination, (2) at least 1 serum sample obtained within 45 days from onset, and (3) complete clinical information. Of 430 participants with acquired demyelinating syndrome recruited, 274 were included in analyses. Of 156 excluded participants, 154 were excluded owing to missing baseline samples and 2 owing to incomplete clinical information. Data were analyzed from May to October 2018.Main outcomes and measuresPresence of anti-MOG antibodies was blindly assessed in serial samples collected over a median of 4 years. Clinical, magnetic resonance imaging, and cerebrospinal fluid features were characterized at presentation, and subsequent disease course was assessed by development of new brain magnetic resonance imaging lesions, total lesion volume at last evaluation, annualized relapse rates, Expanded Disability Status Scale score and visual functional score at 4 years, and any disease-modifying treatment exposure.ResultsOf the 274 included participants, 140 (51.1%) were female, and the median (interquartile range) age of all participants was 10.8 (6.2-13.9) years. One-third of children were positive for anti-MOG antibodies at the time of incident demyelination. Clinical presentations included a combination of optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis for 81 of 84 anti-MOG antibody-positive children (96%). Brain lesions were present in 51 of 76 anti-MOG antibody-positive participants (67%), but magnetic resonance imaging characteristics differed with age at presentation. Complete resolution of baseline lesions was observed in 26 of 49 anti-MOG antibody-positive participants (53%). On serial serum analysis, 38 of 67 participants (57%) who were seropositive at onset became seronegative (median time to conversion, 1 year). Among all participants who were positive for anti-MOG antibodies at presentation, clinical relapses occurred in 9 of 24 children (38%) who remained persistently seropositive and in 5 of 38 children (13%) who converted to seronegative status.Conclusions and relevanceMyelin oligodendrocyte glycoprotein antibodies are common in children with acquired demyelinating syndrome and are transient in approximatively half of cases. Even when persistently positive, most anti-MOG antibody-positive children experience a monophasic disease. The presence of anti-MOG antibodies at the time of incident demyelination should not immediately prompt the initiation of long-term immunomodulatory therapy.

Dataset Information

Tropomyosin Receptor Kinase B Expressed in Oligodendrocyte Lineage Cells Functions to Promote Myelin Following a Demyelinating Lesion.

Publications

Tropomyosin Receptor Kinase B Expressed in Oligodendrocyte Lineage Cells Functions to Promote Myelin Following a Demyelinating Lesion.

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