Biology subjects

Berulava, T.

Publications and source records attributed to Berulava, T..

3 recordsLinked to original sources

bioRxiv2022

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

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. Significance statementThe addition of N6-methyladenosine (m6A) to RNA plays a role in various cellular processes and its de-regulation has been linked to several devastating diseases. The precise role of m6A RNA-methylation in the adult brain is, however, not well understood. In our study, we describe the genome-wide m6A epi-transcriptome in the healthy and diseased brains of mice and humans. Our data demonstrate that a substantial amount of m6A 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 m6A levels specifically impairs synaptic protein-synthesis.

neuroscience↗

bioRxiv2020

The Coding And Small-Non-Coding Hippocampal Synaptic RNAome

Neurons are highly compartmentalized cells that depend on local protein synthesis. Thus, messenger RNAs (mRNAs) have been detected in neuronal dendrites and more recently also at the pre- and postsynaptic compartment. Other RNA species, such as microRNAs, have also been described at synapses where they are believed to control mRNA availability for local translation. Nevertheless, a combined dataset analyzing the synaptic coding and non-coding RNAome via next-generation sequencing approaches is missing. Here we isolate synaptosomes from the hippocampus of young wild type mice and provide the coding and non-coding synaptic RNAome. These data are complemented by a novel approach to analyze the synaptic RNAome from primary hippocampal neurons grown in microfluidic chambers. Our data show that synaptic microRNAs control almost the entire synaptic mRNAome and we identified several hub microRNAs. By combining the in vivo synaptosomal data with our novel microfluidic chamber system, we also provide evidence to support the hypothesis that part of the synaptic microRNAome may be supplied to neurons via astrocytes. Moreover, the microfluidic system is suitable to study the dynamics of the synaptic RNAome in response to stimulation. In conclusion, our data provide a valuable resource and hint to several important targets for future experiments.

neuroscience↗

bioRxiv2020

Epigenetic gene-expression links heart failure to memory impairment

In current clinical practice care of diseased patients is often restricted to separated disciplines. However, such an organ-centered approach is not always suitable. For example, cognitive dysfunction is a severe burden in heart failure patients. Moreover, these patients have an increased risk for age-associated dementias. The underlying molecular mechanisms are presently unknown and thus corresponding therapeutic strategies to improve cognition in heart failure patients are missing. Using mice as model organisms we show that heart failure leads to specific changes in hippocampal gene-expression, a brain region intimately linked to cognition. These changes reflect increased cellular stress pathways which eventually lead to loss of neuronal euchromatin and reduced expression of a hippocampal gene cluster essential for cognition. Consequently, mice suffering from heart failure exhibit impaired memory function. These pathological changes are ameliorated via the administration of a drug that promotes neuronal euchromatin formation. Our study provides first insight to the molecular processes by which heart failure contributes to neuronal dysfunction and point to novel therapeutic avenues to treat cognitive defects in heart failure patients.

neuroscience↗