Animal models of focal ischemic infarcts reveal an impaired GABAergic (gamma-aminobutyric acid) neurotransmission. GABA, the main inhibitory neurotransmitter, is primarily taken up by specific sodium-dependent transporters. As these transporters play a crucial role in maintaining levels of GABA concentration, they may be functionally involved in ischemic processes. We investigated whether the mRNA and protein expression of GAT-1, the dominant neuronal GABA transporter, is altered after cortical infarct induced by photothrombosis in Wistar rats. In situ hybridization was performed to analyze GAT-1 mRNA-positive cells in cortical brain regions and the hippocampus. The lesion dramatically raised the number of GABA transporter mRNA-expressing cells in all investigated cortical regions. Double-labeling studies with a general neuronal marker and a marker for astrocytes revealed that cells expressing GAT-1 mRNA after photothrombosis are neurons. The mRNA expression pattern of all hippocampal subfields remained unchanged. In contrast, cortical GAT-1 protein density was only slightly affected and surprisingly in the opposite way. In the primary and secondary somatosensory cortex, density values were significantly reduced. Immunoreactivity was not altered in all investigated hippocampal areas. We found a marked discordance between the increased number of cells expressing GAT-1 mRNA in the cortex and the reduced tissue GAT-1 protein content. Focal brain ischemia obviously triggers mechanisms that interfere with GAT-1 transcriptional regulation and protein synthesis or turnover.
image This Editorial highlights a study by Kim et al . in the current issue of Journal of Neurochemistry, in which the authors demonstrate that miR‐186 is a potent negative regulator of BACE1 and might be one of the molecular links between advanced brain aging and the increased risk for Alzheimer disease. Read the highlighted article ‘ miR‐186 is decreased in aged brain and suppresses BACE1 expression ’ on page 436 .
Of the around 7,000 known rare diseases worldwide, disease-modifying treatments are available for fewer than 5%, leaving millions of individuals without specialized therapeutic strategies. In recent years, antisense oligonucleotides (ASOs) have shown promise as individualized genetic interventions for rare genetic diseases. However, there is currently no consensus on which disease-causing DNA variants are suitable candidates for this type of genetic therapy. The Patient Identification Working Group of the N=1 Collaborative (N1C), alongside an international group of volunteer assessors, has developed and piloted consensus guidelines for assessing the eligibility of pathogenic variants towards ASO treatments. We herein present the N1C VARIANT ( V ariant A ssessments towa r ds Eligibility for An tisense Oligonucleotide T reatment) guidelines, including the guiding scientific principles and our approach to consensus building. Pathogenic, disease-causing variants can be assessed for the three currently best-established ASO treatment approaches: splice correction, exon skipping, and downregulation of RNA transcripts. A genetic variant is classified as either "eligible", "likely eligible", "unlikely eligible", or "not eligible" in relation to the different approaches, or "unable to assess". We also review key considerations for assessment for upregulation of transcripts from the wildtype allele, an emerging ASO therapeutic strategy. We provide additional tools and training material to enable clinicians and researchers to use these guidelines for their eligibility assessments. With this initial edition of our N1C VARIANT guidelines, we provide the rare genetic disease community with guidance on how to identify suitable candidates for variant-specific ASO-based therapies and the possibility of integrating such assessments into routine clinical practice.
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