Conserved reduction of m ⁶ A RNA modifications during aging and neurodegeneration is linked to changes in synaptic transcripts

Abstract

N 6 -methyladenosine (m 6 A) regulates mRNA metabolism. While it has been implicated in the development of the mammalian brain and in cognition, the role of m 6 A in synaptic plasticity, especially during cognitive decline, is not fully understood. In this study, we employed methylated RNA immunoprecipitation sequencing to obtain the m 6 A epitranscriptome of the hippocampal subregions CA1, CA3, and the dentate gyrus and the anterior cingulate cortex (ACC) in young and aged mice. We observed a decrease in m 6 A levels in aged animals. Comparative analysis of cingulate cortex (CC) brain tissue from cognitively intact human subjects and Alzheimer’s disease (AD) patients showed decreased m 6 A RNA methylation in AD patients. m 6 A changes common to brains of aged mice and AD patients were found in transcripts linked to synaptic function including calcium/calmodulin-dependent protein kinase 2 ( CAMKII ) and AMPA-selective glutamate receptor 1 ( Glua1 ). We used proximity ligation assays to show that reduced m 6 A levels result in decreased synaptic protein synthesis as exemplified by CAMKII and GLUA1. Moreover, reduced m 6 A levels impaired synaptic function. Our results suggest that m 6 A RNA methylation controls synaptic protein synthesis and may play a role in cognitive decline associated with aging and AD.

Dynamics of N6‐methyladenosine modification during aging and their potential roles in the degeneration of intervertebral disc

“…In our study, we performed MeRIP-seq to identify m6A changes in NP tissues at different ages of rats, and found that the number of m6A peaks was 31 986, 32 007, and 19 322 in 2-month-old, 10-month-old, and 20-month-old rats, respectively. The most consensus motif sequence among these three groups was GGACA, similar to the observation in other aged mammals, such as human, 50 and mouse. 52 On one level, this resemblance may elucidate the conserved features of m6A modification in mammals during the progression of aging.…”

“…Interestingly, Castro-Hernández et al demonstrated a decreased m6A level of brain tissues in aged animals and Alzheimer's disease patients. 50 Moreover, a lower level of m6A modification was also detected in the striatum of rat brain undergoing Parkinson's disease. 51 The discrepancies of m6A modification between IDD and neurodegenerative diseases indicate that the level of m6A modification during aging may vary from species, organs, and diseases.…”

The Regulatory Network of METTL3 in the Nervous System: Diagnostic Biomarkers and Therapeutic Targets

“…These findings demonstrate the role of low levels of METTL3 in triggering or exacerbating synaptic plasticity via the ARC-YTHDF1 axis. Moreover, the study from the Ricardo Castro-Hernándeza group reported that neurons with METTL3 knockdown significantly impaired the synaptic translation of calcium/calmodulin-dependent protein kinase 2 (CAMK2) and AMPA-selective glutamate receptor 1 (Glua1) mRNAs [ 25 ]. Consistently, the knockdown of METTL3 was also associated with decreased neuronal activity [ 25 ].…”

“…Moreover, the study from the Ricardo Castro-Hernándeza group reported that neurons with METTL3 knockdown significantly impaired the synaptic translation of calcium/calmodulin-dependent protein kinase 2 (CAMK2) and AMPA-selective glutamate receptor 1 (Glua1) mRNAs [ 25 ]. Consistently, the knockdown of METTL3 was also associated with decreased neuronal activity [ 25 ]. Collectively, these findings provide evidence for the idea that METTL3-mediated down-regulation of the m6A-modification mechanism contributes to synaptic function impairment via impairing the synaptic proteins CAMKII and Glua1 synthesis.…”

Identification of METTL3 as a myeloid-related prognosis biomarker in hepatocellular carcinoma using bioinformatics analysis and engineered mice model

“…The molecular functions of RNA methylation modi cations are involved in RNA metabolism, RNA editing, and RNA structure constructions (5)(6)(7). Physiologically, m6A has been reported to maintain embryonic evolution (8), nervous system development (9), spermatogenesis (10), T cell-mediated adaptive immune response (11), and so on. As an emerging eld of epigenetic modi cation, altered ampli cation or deletion, functional mutation, and aberrant expression of m6A modi cation genes have been observed in cancer (12).…”