m⁶ A mRNA methylation in human brain is disrupted in Lewy body disorders

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 or mild cognitive impairment (MCI).

In non-diseased tissue, we found that m⁶ A-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 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.