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MOBP and HIP1 in multiple system atrophy: new α‐synuclein partners in glial cytoplasmic inclusions implicated in the disease pathogenesis

Bettencourt, C; Miki, Y; Piras, IS; de Silva, R; Foti, SC; Talboom, JS; Revesz, T; ... Holton, JL; + view all (2021) MOBP and HIP1 in multiple system atrophy: new α‐synuclein partners in glial cytoplasmic inclusions implicated in the disease pathogenesis. Neuropathology and Applied Neurobiology , 47 (5) pp. 640-652. 10.1111/nan.12688. Green open access

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Abstract

Aims: MSA is a fatal neurodegenerative disease. Similar to Parkinson’s disease (PD), MSA is an α‐synucleinopathy, and its pathological hallmark consists of glial cytoplasmic inclusions (GCIs) containing α‐synuclein in oligodendrocytes. We previously identified consistent changes in MOBP and HIP1 DNA methylation status in MSA. We hypothesized that if differential DNA methylation at these loci is mechanistically relevant for MSA, it should have downstream consequences on gene regulation. / Methods: We investigated the relationship between MOBP and HIP1 DNA methylation and mRNA levels in cerebellar white matter from MSA and healthy controls. Additionally, we analysed protein expression using western blotting, immunohistochemistry and proximity ligation assays. / Results: We found decreased MOBP mRNA levels significantly correlated with increased DNA methylation in MSA. For HIP1, we found a distinct relationship between DNA methylation and gene expression levels in MSA compared to healthy controls, suggesting this locus may be subjected to epigenetic remodelling in MSA. Although soluble protein levels for MOBP and HIP1 in cerebellar white matter were not significantly different between MSA cases and controls, we found striking differences between MSA and other neurodegenerative diseases, including PD and Huntington’s disease. We also found that MOBP and HIP1 are mislocalized into the GCIs in MSA, where they appear to interact with α‐synuclein. / Conclusions: This study supports a role for DNA methylation in downregulation of MOBP mRNA in MSA. Most importantly, the identification of MOBP and HIP1 as new constituents of GCIs emphasizes the relevance of these two loci to the pathogenesis of MSA.

Type: Article
Title: MOBP and HIP1 in multiple system atrophy: new α‐synuclein partners in glial cytoplasmic inclusions implicated in the disease pathogenesis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/nan.12688
Publisher version: http://dx.doi.org/10.1111/nan.12688
Language: English
Additional information: © 2020 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10118287
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