Search

Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries offer more nuanced and accurate insights into the regulatory mechanisms of RNA editing in the human brain. Adenosine-to-inosine editing is a form of RNA modification observed in the human brain transcriptome. Here the authors question the accuracy of utilizing postmortem samples to reflect the RNA biology of living brains. This is due to significant differences in adenosine-to-inosine editing between living and postmortem brain tissues, with most sites exhibiting higher editing levels postmortem. [ABSTRACT FROM AUTHOR]

This correction notice is for an article titled "Divergent landscapes of A-to-I editing in postmortem and living human brain" published in Nature Communications. The correction addresses an error in the Competing Interests statement, which incorrectly stated that the authors had no competing interests. The corrected statement reveals the competing interests of some authors, including their affiliations with various companies and organizations. The correction was made by Miguel Rodriguez de los Santos, Brian H. Kopell, Panos Roussos, Alexander W. Charney, and Michael S. Breen. [Extracted from the article]

The progressive and permanent loss of cerebellar Purkinje cells (PC) is a hallmark of many inherited ataxias. Mutations in several genes involved in the regulation of Ca release from intracellular stores by the second messenger IP have been associated with PC dysfunction or death. While much is known about the defects in production and response to IP, less is known about the defects in breakdown of the IP second messenger. A mutation in Inpp4a of the pathway is associated with a severe, early-onset PC degeneration in the mouse model weeble. The step preceding the removal of the 4-phosphate is the removal of the 5-phosphate by Inpp5a. Gene expression analysis was performed on an Inpp5a mouse generated by gene trap insertion using quantitative real-time PCR (qRT-PCR), immunohistochemistry, and Western blot. Phenotypic analyses were performed using rotarod, β-galactosidase staining, and phosphatase activity assay. Statistical significance was calculated. The deletion of Inpp5a causes an early-onset yet slowly progressive PC degeneration and ataxia. Homozygous mutants (90 %) exhibit perinatal lethality; surviving homozygotes show locomotor instability at P16. A consistent pattern of PC loss in the cerebellum is initially detectable by weaning and widespread by P60. Phosphatase activity toward phosphoinositol substrates is reduced in the mutant relative to littermates. The ataxic phenotype and characteristics neurodegeneration of the Inpp5a mouse indicate a crucial role for Inpp5a in PC survival. The identification of the molecular basis of the selective PC survival will be important in defining a neuroprotective gene applicable to establishing a disease mechanism. [ABSTRACT FROM AUTHOR]

The identification of novel mutant alleles is important for understanding critical functional domains of a protein and establishing genotype:phenotype correlations. The recoil wobbler ( rcw) allelic series of spontaneous ataxic mutants and the ENU-induced mutant nmf373 genetically mapped to a shared region of chromosome 10. Their mutant phenotypes are strikingly similar; all have an ataxic phenotype that is recessive, early-onset, and is not associated with neurodegeneration. In this study we used complementation tests to show that these series of mutants are allelic to a knockout mutant of Grm1. Subsequently, a duplication of exon 4 and three missense mutations were identified in Grm1: I160T, E292D, and G337E. All mutations occurred within the ligand-binding region and changed conserved amino acids. In the rcw mutant, the Grm1 gene is expressed and the protein product is properly localized to the molecular layer of the cerebellar cortex. Grm1 is responsible for the generation of inositol 1,4,5-trisphosphate (IP3). The inositol second messenger system is the central mechanism for calcium release from intracellular stores in cerebellar Purkinje cells. Several of the genes involved in this pathway are mutated in mouse ataxic disorders. The novel rcw mutants represent a resource that will have utility for further studies of inositol second-messenger-system defects in neurogenetic disorders. [ABSTRACT FROM AUTHOR]

The soluble N-ethylmaleimide sensitive factor attachment receptors are a large family of membrane-associated proteins that are critical for Ca2+-mediated synaptic vesicle release. This family includes the VAMP, synaptosomal-associated protein, and syntaxin proteins. In this report, we describe a mutation in vesicle-associated membrane protein 1( VAMP1)/synaptobrevin in the mouse neurological mutant lethal-wasting ( lew). The lethal-wasting mutant phenotype is characterized by a general lack of movement and wasting, eventually leading to death before weaning. Mutants are visibly immobile and lay on their side by postnatal day 10 (P10). Before this stage, mutants can be identified by a failure to attempt to right themselves. Affected mice die on average at P15. We used a positional cloning strategy to identify the mutation associated with this neurological phenotype. Lethal wasting had previously been linked to chromosome 6. We further narrowed the genetic disease interval and selected a small number of candidate genes for mutation screening. Genes were evaluated by quantitative reverse transcription–polymerase chain reaction (RT–PCR) to detect differences in their expression levels between control and mutant brain ribonucleic acid (RNA) samples. VAMP1 mRNA was found to be significantly downregulated in the lethal-wasting brain compared to wild-type littermates. Subsequently, a nonsense mutation was identified in the coding region of the gene. This mutation is predicted to truncate approximately half of the protein; however, Western blot analysis showed that no protein is detectable in the mutant. VAMP1 is selectively expressed in the retina and in discrete areas of the brain including the zona incerta and rostral periolivary region, although no gross histological abnormalities were observed in these tissues. Taken together, these data indicate that VAMP1 has a vital role in a subset of central nervous system tissues. [ABSTRACT FROM AUTHOR]