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

Abstract

AbstractAimsN6‐methyladenosine modification of RNA (m6A) regulates translational control, which may influence neuronal dysfunction underlying neurodegenerative diseases.MethodsUsing 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 or mild cognitive impairment (MCI).ResultsIn non‐diseased tissue, we found that m6A‐modified RNAs showed cell‐type and sub‐compartment‐specific variation. YTHDF1 and YTHDF3 showed opposing expression patterns in the cerebellum and the 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.ConclusionsThese 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.