Global Co-regulatory Cross Talk Between mA and mC RNA Methylation Systems Coordinate Cellular Responses and Brain Disease Pathways.

N6 adenosine and C5 cytosine modification of mRNAs, tRNAs and rRNAs are regulated by the behaviour of distinct sets of writer, reader and eraser effector proteins which are conventionally considered to function independently. Here, we provide evidence of global cross-regulatory and functional interaction between the mA and mC RNA methylation systems. We first show that mA and mC effector protein transcripts are subject to reciprocal base modification supporting the existence of co-regulatory post-transcriptional feedback loops.

Dysregulation of RNA modification systems in clinical populations with neurocognitive disorders.

The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms. Methylation of N6 adenosine (m6A) and C5 cytosine (m5C) bases occur on mRNAs, tRNA, mt-tRNA, and rRNA species as well as non-coding RNAs. With emerging knowledge of RNA binding proteins that act as writer, reader, and eraser effector proteins, comes a new understanding of physiological processes controlled by these systems.

Extracellular vesicle microRNA-mediated transcriptional regulation may contribute to dementia with Lewy bodies molecular pathology.

Objective: Dementia with Lewy bodies (DLB) is the second most common dementia. Advancing our limited understanding of its molecular pathogenesis is essential for identifying novel biomarkers and therapeutic targets for DLB. DLB is an α-synucleinopathy, and small extracellular vesicles (SEV) from people with DLB can transmit α-synuclein oligomerisation between cells.

The importance of mA topology in chicken embryo mRNA: a precise mapping of mA at the conserved chicken β-actin zipcode.

-methyladenosine (mA) in mRNA regulates almost every stage in the mRNA life cycle, and the development of methodologies for the high-throughput detection of methylated sites in mRNA using mA-specific methylated RNA immunoprecipitation with next-generation sequencing (MeRIPSeq) or mA individual-nucleotide-resolution cross-linking and immunoprecipitation (miCLIP) have revolutionized the mA research field. Both of these methods are based on immunoprecipitation of fragmented mRNA. However, it is well documented that antibodies often have nonspecific activities, thus verification of identified mA sites using an antibody-independent method would be highly desirable.

m A mRNA methylation in human brain is disrupted in Lewy body disorders.

Aims: N -methyladenosine modification of RNA (m A) regulates translational control, which may influence neuronal dysfunction underlying neurodegenerative diseases.

Methods: Using microscopy and a machine learning approach, we performed cellular profiling of m A-RNA abundance and YTHDF1/YTHDF3 m A reader expression within four regions of the human brain from non-affected individuals and individuals with Parkinson's disease, dementia with Lewy bodies or mild cognitive impairment (MCI).

Results: In non-diseased tissue, we found that m A-modified RNAs showed cell-type and sub-compartment-specific variation.

Differential expression of mC RNA methyltransferase genes NSUN6 and NSUN7 in Alzheimer's disease and traumatic brain injury.

Epigenetic processes have become increasingly relevant in understanding disease-modifying mechanisms. 5-Methylcytosine methylations of DNA (5mC) and RNA (mC) have functional transcriptional and RNA translational consequences and are tightly regulated by writer, reader and eraser effector proteins. To investigate the involvement of 5mC/5hmC and mC effector proteins contributing to the development of dementia neuropathology, RNA sequencing data of 31 effector proteins across four brain regions was examined in 56 aged non-affected and 51 Alzheimer's disease (AD) individuals obtained from the Aging, Dementia and Traumatic Brain Injury Study.

Modifying the mA brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging.

Synaptic plasticity processes, which underlie learning and memory formation, require RNA to be translated local to synapses. The synaptic tagging hypothesis has previously been proposed to explain how mRNAs are available at specific activated synapses. However how RNA is regulated, and which transcripts are silenced or processed as part of the tagging process is still unknown.

Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities.

Schizophrenia (Scz), autism spectrum disorder (ASD) and intellectual disability are common complex neurodevelopmental disorders. Kainate receptors (KARs) are ionotropic glutamate ion channels involved in synaptic plasticity which are modulated by auxiliary NETO proteins. Using UK10K exome sequencing data, we interrogated the coding regions of KAR and NETO genes in individuals with Scz, ASD or intellectual disability and population controls; performed follow-up genetic replication studies; and, conducted in silico and in vitro functional studies.

Interaction of nutrition and genetics via DNMT3L-mediated DNA methylation determines cognitive decline.

Low homocysteine levels and B vitamin treatment are reported to protect against declining cognitive health. Both B vitamins and homocysteine are involved in the production of S-adenosylmethionine, a universal methyl donor essential for the process of DNA methylation. We investigated the effect of a damaging coding variant within the DNA methyltransferase gene DNMT3L (R278G, A/G) by examining B vitamin intake, homocysteine levels, cognitive performance, and brain atrophy in individuals in the VITACOG study of mild cognitive impairment and the TwinsUK cohort.

A kainate receptor GluK4 deletion, protective against bipolar disorder, is associated with enhanced cognitive performance across diagnoses in the TwinsUK cohort.

Cognitive deficits are a common feature of neuropsychiatric disorders. We investigated the relationship between cognitive performance and a deletion allele within GluK4 protective against risk for bipolar disorder, in 1,642 individuals from the TwinsUK study. Cognitive performance was assessed using the National Adult Reading Test, four CANTAB tests (Spatial Working Memory, Paired Associates Learning, Pattern Recognition Memory and Reaction Time), and two Principal-Component Analysis-derived factors.

Vitamin intake is associated with improved visuospatial and verbal semantic memory in middle-aged individuals.

Objectives: Factors maintaining cognitive health are still largely unknown. In particular, the cognitive benefits associated with vitamin intake and vitamin supplementation are disputed. We investigated self-reported vitamin intake and serum vitamin levels with performance in cognitive factors sensitive to dementia progression in two large middle-aged general population cohorts.

Cognitive endophenotypes in a family with bipolar disorder with a risk locus on chromosome 4.

Objectives:   We studied cognitive function in high-risk relatives belonging to a single extended family showing linkage of bipolar disorder to a locus on chromosome 4. High-risk relatives were defined as those that carried the risk haplotype of polymorphic markers, identified in a previous linkage study. This family provided a rare opportunity to characterize a neuropsychological endophenotype in a homogeneous sample of relatives with a common genetic risk factor.

GRIK4/KA1 protein expression in human brain and correlation with bipolar disorder risk variant status.

The kainate class of ionotropic glutamate receptors is involved in the regulation of neuronal transmission and synaptic plasticity. Previously we reported that a deletion variant within the gene GRIK4, which encodes the KA1 kainate receptor subunit, was associated with a reduced risk of bipolar disorder and increased GRIK4 mRNA abundance. Using a high resolution immunohistochemistry technique, we characterized KA1 protein localization in human brain and performed a genotype-protein expression correlation study.

A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression.

Schizophrenia and bipolar disorder are leading causes of morbidity across all populations, with heritability estimates of approximately 80% indicating a substantial genetic component. Population genetics and genome-wide association studies suggest an overlap of genetic risk factors between these illnesses but it is unclear how this genetic component is divided between common gene polymorphisms, rare genomic copy number variants, and rare gene sequence mutations. We report evidence that the lipid transporter gene ABCA13 is a susceptibility factor for both schizophrenia and bipolar disorder.

Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment.

Homozygosity mapping within consanguineous families is a powerful method of localising genes for autosomal recessive disease. We investigated a family from Punjab, Pakistan, a region where consanguineous marriages are frequent. The parents have no detectable clinical disorders.