Analysis of the Circular Transcriptome in the Synaptosomes of Aged Mice.

Recently, circular RNAs (circRNAs) have been revealed to be an important non-coding element of the transcriptome. The brain contains the most abundant and widespread expression of circRNA. There are also indications that the circular transcriptome undergoes dynamic changes as a result of brain ageing. Diminished cognitive function with increased age reflects the dysregulation of synaptic function and ineffective neurotransmission through alterations of the synaptic proteome. Here, we present changes in the circular transcriptome in ageing synapses using a mouse model. Specifically, we observed an accumulation of uniquely expressed circular transcripts in the synaptosomes of aged mice compared to young mice. Individual circRNA expression patterns were characterized by an increased abundance in the synaptosomes of young or aged mice, whereas the opposite expression was observed for the parental gene linear transcripts. These changes in expression were validated by RT-qPCR. We provide the first comprehensive survey of the circular transcriptome in mammalian synapses, thereby paving the way for future studies. Additionally, we present 16 genes that express solely circRNAs, without linear RNAs co-expression, exclusively in young and aged synaptosomes, suggesting a synaptic gene network that functions along canonical splicing activity.

RNA sequencing reveals pronounced changes in the noncoding transcriptome of aging synaptosomes.

Normal aging is associated with impairments in cognitive functions. These alterations are caused by diminutive changes in the biology of synapses, and ineffective neurotransmission, rather than loss of neurons. Hitherto, only a few studies, exploring molecular mechanisms of healthy brain aging in higher vertebrates, utilized synaptosomal fractions to survey local changes in aging-related transcriptome dynamics. Here we present, for the first time, a comparative analysis of the synaptosomes transcriptome in the aging mouse brain using RNA sequencing. Our results show changes in the expression of genes contributing to biological pathways related to neurite guidance, synaptosomal physiology, and RNA splicing. More intriguingly, we also discovered alterations in the expression of thousands of novel, unannotated lincRNAs during aging. Further, detailed characterization of the cleavage and polyadenylation factor I subunit 1 (Clp1) mRNA and protein expression indicates its increased expression in neuronal processes of hippocampal stratum radiatum in aging mice. Together, our study uncovers a new layer of transcriptional regulation which is targeted by aging within the local environment of interconnecting neuronal cells.