In Neuropathology and applied neurobiology ; h5-index 39.0
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.
De La Cruz Braulio Martinez, Gell Chris, Markus Robert, Macdonald Ian, Fray Rupert, Knight Helen Miranda
2023-Jan-29
Dementia with Lewis bodies, Epitranscriptomics, Lewy body Disease, Mild Cognitive Impairment, Parkinson’s disease, RNA methylation, m6A
