Conserved reduction of m⁶A marks during aging and neurodegeneration is linked to altered translation of synaptic transcripts

Abstract

N6-methyladenosine (m6A) 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 m6A in the context synaptic plasticity and especially during impaired cognition are not fully understood. Here, we describe the mouse and human brain m6A 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 N6-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 m6A-RNA-methylation is an important mechanism to control synaptic protein synthesis which is affected early in cognitive diseases.

N6-methyladenosine (m6A) RNA modification as a metabolic switch between plant cell survival and death in leaf senescence

“…The research has shown the possibility of the existence of complex senescence regulatory mechanisms including RNA modifications (Sobieszczuk-Nowicka et al, 2018); therefore, investigation of the epigenetic mechanisms participating in leaf senescence is an important research topic. As has already been mentioned the role of m 6 A modifications in the aging of animal models as well as cell senescence has been previously reported (Castro-Hernańdez et al, 2022;Sun et al, 2022b). Recent findings about m 6 A modification in the process of aging include the participation of this modification in cell senescence, inflammation, autophagy, DNA damage, oxidative stress, neurodegenerative diseases, tumors, diabetes, and cardiovascular diseases.…”