N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer's disease

Abstract

Background Synaptic degeneration occurs in the early stage of Alzheimer's disease (AD) before devastating symptoms, strongly correlated with cognitive decline. Circular RNAs (circRNAs) are abundantly enriched in neural tissues, and aberrant expression of circRNAs precedes AD symptoms, significantly correlated with clinical dementia severity. However, the direct relationship between circRNA dysregulation and synaptic impairment in the early stage of AD remains poorly understood. Methods Hippocampal whole-transcriptome sequencing was performed to identify dysregulated circRNAs and miRNAs in 4-month-old wild-type and APP/PS1 mice. RNA antisense purification and mass spectrometry were utilized to unveil interactions between circRIMS2 and methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3). The roles of circRIMS2/miR-3968 in synaptic targeting of UBE2K-mediated ubiquitination of GluN2B subunit of NMDA receptor were evaluated via numerous lentiviruses followed by morphological staining, co-immunoprecipitation and behavioral testing. Further, a membrane-permeable peptide was used to block the ubiquitination of K1082 on GluN2B in AD mice. Results circRIMS2 was significantly upregulated in 4-month-old APP/PS1 mice, which was mediated by METTL3-dependent N6-methyladenosine (m6A) modification. Overexpression of circRIMS2 led to synaptic and memory impairments in 4-month-old C57BL/6 mice. MiR-3968/UBE2K was validated as the downstream of circRIMS2. Elevated UBE2K induced synaptic dysfunction of AD through ubiquitinating K1082 on GluN2B. Silencing METTL3 or blocking the ubiquitination of K1082 on GluN2B with a short membrane-permeable peptide remarkably rescued synaptic dysfunction in AD mice. Conclusions In conclusion, our study demonstrated that m6A-modified circRIMS2 mediates the synaptic and memory impairments in AD by activating the UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968, providing novel therapeutic strategies for AD.

Emerging Roles and Mechanisms of RNA Modifications in Neurodegenerative Diseases and Glioma

“…For circRNA, high-throughput sequencing has revealed significant changes in circRNA m6A methylation in APP/PS1 AD mice compared to control groups [ 76 ]. This result was consistent with another group’s study where METTL3-dependent m6A-modified circular RNA, circRIMS2, was significantly upregulated in APP/PS1 AD mice, which mediated synaptic and memory impairments by activating the ubiquitination of the GluN2B subunit of the NMDA receptor [ 77 ]. Silencing METTL3 or hindering the GluN2B ubiquitination by a short membrane-permeable peptide significantly rescued synaptic impairment in APP/PS1 AD mice.…”

Fibroblast-like synoviocytes-derived exosomal circFTO deteriorates rheumatoid arthritis by enhancing N6-methyladenosine modification of SOX9 in chondrocytes

“…Additionally, Hu et al propose that WTAP-mediated m6a modification contributes to improved stability for circCCAR1 [ 24 ]. Furthermore, METTL3 has been observed regulating various circRNAs such as cirRIMS2 [ 25 ], circPRKAR1B [ 26 ], and cirQSOX1 [ 27 ] through its involvement in mediating m6A methylation. Considering these findings, we hypothesized that circFTO may interact with MTC to influence self-methylation or modifying other RNAs.…”

Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases

“…BACE1 SUMOylation is a reciprocal regulator of its phosphorylation and ubiquitination, which may have implications for the regulation of BACE1 activity and Aβ accumulation in Alzheimer’s disease [ 31 ]. N6-methyladenosine(m6A)-modified circRIMS2 contributes to synaptic and memory impairments in AD by regulating GluN2B ubiquitination [ 32 ].…”