DNA methylation in demyelinated multiple sclerosis hippocampus

Chomyk, Anthony M.; Volsko, Christina; Tripathi, Ajai K.; Deckard, Sadie A.; Trapp, Bruce D.; Fox, Robert J.; Dutta, Ranjan

doi:10.1038/s41598-017-08623-5

Cited by 59 publications

(50 citation statements)

References 44 publications

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“…Epigenetic mechanisms (e.g., DNA methylation) have been shown to alter gene expression in the hippocampus of MS patients. 23 Whether these mechanisms are involved in the pathogenesis or represent a secondary consequence of demyelination remains to be defined.…”

Section: Pathological Basis Of Hippocampal Damage In Msmentioning

confidence: 99%

The hippocampus in multiple sclerosis

Rocca

Barkhof

Luca

et al. 2018

The Lancet Neurology

108

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Some of the clinical manifestations of multiple sclerosis, such as memory impairment and depression, are, at least partly, related to involvement of the hippocampus. Pathological studies have shown extensive demyelination, neuronal damage, and synaptic abnormalities in the hippocampus of patients with multiple sclerosis, and improvements in MRI technology have provided novel ways to assess hippocampal involvement in vivo. It is now accepted that clinical manifestations related to the hippocampus are due not only to focal hippocampal damage, but also to disconnection of the hippocampus from several brain networks. Evidence suggests anatomical and functional subspecialisation of the different hippocampal subfields, resulting in variability between regions in the extent to which damage and repair occur. The hippocampus also has important roles in plasticity and neurogenesis, both of which potentially contribute to functional preservation and restoration. These findings underline the importance of evaluation of the hippocampus not only to improve understanding of the clinical manifestations of multiple sclerosis, but also as a potential future target for treatment.

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Section: Pathological Basis Of Hippocampal Damage In Msmentioning

confidence: 99%

The hippocampus in multiple sclerosis

Rocca

Barkhof

Luca

et al. 2018

The Lancet Neurology

108

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“…Brainstem and spinal cord tissue from MS patients were collected according to the established rapid autopsy protocol approved by the Cleveland Clinic Institutional Review Board (114). Tissue was removed, fixed in 4% paraformaldehyde and sectioned.…”

Section: Methodsmentioning

confidence: 99%

Regional astrocyte interferon-γ signaling regulates immunoproteasome-mediated protection during chronic autoimmunity

Sinyuk

et al. 2019

Preprint

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17In early autoimmune neuroinflammation, interferon (IFN)g and its upregulation of the 18 immunoproteasome (iP) is pathologic. However, during chronic multiple sclerosis (MS), IFNg has 19 protective properties and, the role of the iP remains to be fully elucidated. Here, we demonstrated 20 that IFNg signaling in regional astrocytes induces the iP and protects the CNS during 21 autoimmunity. In MS tissue, iP expression was enhanced in spinal cord compared to brainstem 22 lesions, which correlated with a decrease in oxidative stress. In vitro, IFNg stimulation enhanced 23 iP expression, reduced reactive oxygen species burden, and decreased oxidatively damaged and 24 poly-ubiquitinated protein accumulation preferentially in human spinal cord astrocytes, which was 25 abrogated with the use of the iP inhibitor, ONX 0914. During the chronic phase of an MS animal 26 model, experimental autoimmune encephalomyelitis (EAE), ONX 0914 treatment exacerbated 27 disease and led to increased oxidative stress and poly-ubiquitinated protein build-up. Finally, mice 28 with astrocyte-specific loss of the IFNg receptor exhibited worsened chronic EAE associated with 29 reduced iP expression, enhanced lesion size and oxidative stress and poly-ubiquitinated protein 30 accumulation in astrocytes. Taken together, our data reveal a protective role for IFNg in chronic 31 neuroinflammation and identify a novel function of the iP in astrocytes during CNS autoimmunity. 32 33 34 Multiple sclerosis (MS) is the most common chronic inflammatory and 35 neurodegenerative disease of the central nervous system (CNS) (1). During the 36 pathogenesis of MS, there is immune cell infiltration, demyelination, and reactive gliosis 37within CNS lesions in multiple regions (2). Relapsing-remitting MS (RRMS) is a subtype 38 that affects approximately 85% of patients and is characterized by episodic periods of 39 neurological dysfunction, often associated with inflammation, followed by partial or 40 complete recovery. A significant proportion of these patients go on to develop secondary 41 progressive MS (SPMS), during which they have fewer remissions and increasing 42 atrophy, correlating with progressive disability (3, 4). Primary progressive (PPMS) a third 43 subtype of MS, affects approximately 15% of patients and is associated with continuous, 44 progressive loss of neurological function after initial diagnosis, without periods of 45 remission (5, 6). Of note, it is thought that the pathology associated with RRMS has a 46 relatively significant inflammatory component, while in SPMS and PPMS, inflammation is 47 an animal model of MS, astrocytes are known to exhibit regional heterogeneity in gene 58 expression and response to inflammation (17)(18)(19). Indeed, ablation of astrocytes following 59 several types of CNS injury leads to sustained inflammation, impaired repair, and 60 increased neurodegeneration (20-29), suggesting that a diverse astrocytic response is 61 critical in healthy tissue preservation and support, minimizing CNS bystander damage 62 during...

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“…This is followed by collection of 3-4 subsequent sections, separation from the adjoining tissues, and storage for DNA, RNA, or protein isolation. Using this protocol, we have successfully isolated DNA 24,25 , RNA 5,6,7,8,9 as well as proteins 26 . While major findings from some of the studies analyzing RNA from MS brains are discussed, here are some of the issues related to analysis of RNA postmortem MS brains.…”

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confidence: 99%

Comprehensive Autopsy Program for Individuals with Multiple Sclerosis

Dutta

Mahajan

Nakamura

et al. 2019

JoVE

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We describe a rapid tissue donation program for individuals with multiple sclerosis (MS) that requires scientists and technicians to be on-call 24/7, 365 days a year. Participants consent to donate their brain and spinal cord. Most patients were followed by neurologists at the Cleveland Clinic Mellen Center for MS Treatment and Research. Their clinical courses and neurological disabilities are well-characterized. Soon after death, the body is transported to the MS Imaging Center, where the brain is scanned in situ by 3 T magnetic resonance imaging (MRI). The body is then transferred to the autopsy room, where the brain and spinal cord are removed. The brain is divided into two hemispheres. One hemisphere is immediately placed in a slicing box and alternate 1 cm-thick slices are either fixed in 4% paraformaldehyde for two days or rapidly frozen in dry ice and 2-methylbutane. The short-fixed brain slices are stored in a cryopreservation solution and used for histological analyses and immunocytochemical detection of sensitive antigens. Frozen slices are stored at-80 °C and used for molecular, immunocytochemical, and in situ hybridization/RNA scope studies. The other hemisphere is placed in 4% paraformaldehyde for several months, placed in the slicing box, re-scanned in the 3 T magnetic resonance (MR) scanner and sliced into centimeter-thick slices. Postmortem in situ MR images (MRIs) are coregistered with 1 cm-thick brain slices to facilitate MRI-pathology correlations. All brain slices are photographed and brain white-matter lesions are identified. The spinal cord is cut into 2 cm segments. Alternate segments are fixed in 4% paraformaldehyde or rapidly frozen. The rapid procurement of postmortem MS tissues allows pathological and molecular analyses of MS brains and spinal cords and pathological correlations of brain MRI abnormalities. The quality of these rapidly-processed postmortem tissues (usually within 6 h of death) is of great value to MS research and has resulted in many high-impact discoveries. Video Link The video component of this article can be found at https://www.jove.com/video/59511/ Recruitment Donations are obtained through either ante-mortem consent obtained directly from patients (pre-consented) or from next of kin after death. Pre-consented patients are typically identified from the clinical population at the Mellen Center for Multiple Sclerosis Treatment and Research

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DNA methylation in demyelinated multiple sclerosis hippocampus

Cited by 59 publications

References 44 publications

The hippocampus in multiple sclerosis

The hippocampus in multiple sclerosis

Regional astrocyte interferon-γ signaling regulates immunoproteasome-mediated protection during chronic autoimmunity

Comprehensive Autopsy Program for Individuals with Multiple Sclerosis

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