Work

Conserved reduction of m 6 A marks during aging and neurodegeneration is linked to altered translation of synaptic transcripts

Year: 2022

Type: preprint

Abstract: N 6 -methyladenosine (m 6 A) plays diverse roles in the regulation of mRNA metabolism. In the mammalian brain it has been linked to developmental processes and memory function. However, the precise role of m 6 A in the context synaptic plasticity and especially during impaired cognition are not fully understood. Here, we describe the mouse and human brain m 6 A epi-transcriptome in a tissue-specific manner. We furthermore show that m6A levels undergo a massive decrease across mouse brain regions as a consequence of aging. In addition, Alzheimer's disease in humans correlates with decreased N 6 -methylation in a similar population of transcripts that are linked to synaptic function and localized to synapses, such as the calcium/calmodulin-dependent kinase II (CaMKII). We furthermore show that reduced m6A levels impair synaptic protein-synthesis of CAMKII. Our results suggest that m 6 A-RNA-methylation is an important mechanism to control synaptic protein synthesis which is affected early in cognitive diseases. Significance statement The addition of N 6 -methyladenosine (m 6 A) to RNA plays a role in various cellular processes and its de-regulation has been linked to several devastating diseases. The precise role of m 6 A RNA-methylation in the adult brain is, however, not well understood. In our study, we describe the genome-wide m 6 A epi-transcriptome in the healthy and diseased brains of mice and humans. Our data demonstrate that a substantial amount of m 6 A transcripts are conserved. These transcripts are linked to the regulation of synaptic processes and are localized to synapses. In the diseases brain we detect RNA hypomethylation across multiple transcripts in all investigated brain regions and across species. At the mechanistic level we find that reduced m 6 A levels specifically impairs synaptic protein-synthesis.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.1101/2022.06.08.495100