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m6A mRNA methylation in human brain is disrupted in Lewy body disorders

De La Cruz, Braulio Martinez; Gell, Chris; Markus, Robert; Macdonald, Ian; Fray, Rupert; Knight, Helen Miranda; (2023) m6A mRNA methylation in human brain is disrupted in Lewy body disorders. Neuropathology and Applied Neurobiology , 49 (1) , Article e12885. 10.1111/nan.12885. Green open access

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Abstract

N6-methyladenosine modification of RNA (m6 A) regulates translational control which may influence neuronal dysfunction underlying neurodegenerative diseases. Using microscopy and a machine learning approach, we performed cellular profiling of m6 A-RNA abundance and YTHDF1/YTHDF3 m6 A reader expression within four regions of the human brain from non-affected individuals and individuals with Parkinson's disease, Dementia with Lewy bodies (DLB) or Mild Cognitive Impairment (MCI). In non-diseased tissue, we found m6 A-modified RNAs showed cell-type and sub-compartment-specific variation. YTHDF1 and YTHDF3 showed opposing expression patterns in the cerebellum, and frontal and cingulate cortices. Machine learning quantitative image analysis revealed that m6 A-modified transcripts were significantly altered in localisation and abundance in disease tissue with significant decreases in m6 A-RNAs in Parkinson's disease, and significant increases in m6 A-RNA abundance in Dementia with Lewy bodies. MCI tissue showed variability across regions but similar to DLB, in brain areas with an overall significant increase in m6 A-RNAs, modified RNAs within dendritic processes were reduced. Using mass spectrometry proteomic datasets to corroborate our findings, we found significant changes in YTHDF3 and m6 A anti-reader protein abundance in Alzheimer's disease (AD) and asymptomatic AD/MCI tissue and correlation with cognitive resilience. These results provide evidence for disrupted m6 A regulation in Lewy body diseases and a plausible mechanism through which RNA processing could contribute to the formation of Lewy bodies and other dementia-associated pathological aggregates. The findings suggest that manipulation of epitranscriptomic processes influencing translational control may lead to new therapeutic approaches for neurodegenerative diseases.

Type: Article
Title: m6A mRNA methylation in human brain is disrupted in Lewy body disorders
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/nan.12885
Publisher version: https://doi.org/10.1111/nan.12885
Language: English
Additional information: Copyright © 2023 The Authors. 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.
Keywords: Dementia with Lewis bodies, Epitranscriptomics, Lewy body Disease, Mild Cognitive Impairment, Parkinson’s disease, RNA methylation, m6A
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 Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10165049
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