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

Martinez De La Cruz, Braulio; Gell, Chris; Markus, Robert; Macdonald, Ian; Fray, Rupert; Knight, Helen Miranda


Braulio Martinez De La Cruz

Chris Gell

Robert Markus

Ian Macdonald

Professor of Epitranscriptomics



N6-methyladenosine modification of RNA (m6A) regulates translational control which may influence neuronal dysfunction underlying neurodegenerative diseases. Using microscopy and a machine learning approach, we performed cellular profiling of m6A-RNA abundance and YTHDF1/YTHDF3 m6A 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 m6A-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 m6A-modified transcripts were significantly altered in localisation and abundance in disease tissue with significant decreases in m6A-RNAs in Parkinson’s disease, and significant increases in m6A-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 m6A-RNAs, modified RNAs within dendritic processes were reduced. Using mass spectrometry proteomic datasets to corroborate our findings, we found significant changes in YTHDF3 and m6A 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 m6A 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.


Martinez De La Cruz, B., Gell, C., Markus, R., Macdonald, I., Fray, R., & Knight, H. M. (2023). m6A mRNA methylation in human brain is disrupted in Lewy body disorders. Neuropathology and Applied Neurobiology, 49(1), Article e12885.

Journal Article Type Article
Acceptance Date Dec 13, 2022
Online Publication Date Feb 27, 2023
Publication Date 2023-02
Deposit Date Feb 1, 2023
Publicly Available Date Jan 30, 2024
Journal Neuropathology and Applied Neurobiology
Print ISSN 0305-1846
Electronic ISSN 1365-2990
Peer Reviewed Peer Reviewed
Volume 49
Issue 1
Article Number e12885
Public URL
Publisher URL


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