Dominant mutations in the ubiquitous enzyme glycyl‐tRNA synthetase (GlyRS), including S581L, lead to motor nerve degeneration. We have determined crystal structures of wildtype and S581L‐mutant human GlyRS. The S581L mutation is ∼50 Å from the active site, and yet gives reduced aminoacylation activity. The overall structures of wildtype and S581L‐GlyRS, including the active site, are very similar. However, residues 567–575 of the anticodon‐binding domain shift position and in turn could indirectly affect glycine binding via the tRNA or alternatively inhibit conformational changes. Reduced enzyme activity may underlie neuronal degeneration, although a dominant‐negative effect is more likely in this autosomal dominant disorder.
Abstract Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine ( N cases / N controls = 59,674/316,078) and BP ( N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, r g = 0.11, P = 3.56 × 10 −06 ) and systolic BP (SBP, r g = 0.06, P = 0.01), but not pulse pressure (PP, r g = −0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci ( P ≤ 5 × 10 −08 ), nine of which replicate ( P < 0.05) in the UK Biobank. Five shared loci ( ITGB5 , SMG6 , ADRA2B , ANKDD1B , and KIAA0040 ) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15–1.25]/10 mmHg; P = 5.57 × 10 −25 ) on migraine than SBP (1.05 [1.03–1.07]/10 mmHg; P = 2.60 × 10 −07 ) and a corresponding opposite effect for PP (0.92 [0.88–0.95]/10 mmHg; P = 3.65 × 10 −07 ). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine.
Two microsatellite markers, tightly linked to CACNA1A, were genotyped in migraine with aura (MA) families to determine if this gene, which underlies the 19p13 linked forms of familial hemiplegic migraine, is also linked to MA. Two-point parametric lod and nonparametric linkage scores did not support linkage. Transmission disequilibrium testing provided no evidence for linkage of MA to CACNA1A. In a large dataset of 64 Canadian MA families, the authors did not find evidence to support an MA susceptibility gene in the region of 19p13.
Two-pore domain K+ (K2P) channels generate K+ leak current, which serves a vital role in controlling and modulating neuronal excitability. This diverse family of K+ channels exhibit distinct expression and function across neuronal tissues. TWIK-related spinal cord K+ channel (TRESK) is a K2P channel with a particularly enriched role in sensory neurons and in vivo pain pathways. Here, we explored the role of TRESK across molecularly distinct sensory neuron populations and assessed its contribution to different sensory modalities. We found TRESK mRNA only in select populations of C- and A-δ nociceptors, in addition to low threshold D-hair afferents. Neurons from mice in which TRESK has been ablated demonstrated marked hyperexcitability, which was amplified under inflammatory challenge. Detailed behavioural phenotyping of TRESK knockout mice revealed specific deficits in somatosensory processing of noxious and non-noxious stimuli. These results demonstrate novel roles of TRESK in somatosensory processing and offer important information to those wishing to target the channel for therapeutic means.
Abstract The suprachiasmatic nucleus (SCN), the mammalian circadian clock, is a heterogenous structure made of several neuron types that generate a circadian electrical activity profile. However, it is unclear how such regulation in endogenous neuronal excitability is maintained. Background two-pore domain potassium channels (K2P), such as TASK-3, play an important role in inhibiting neuronal activity. Here, we utilize a TASK-3 KO mouse model to unravel the role played by this channel in SCN circadian neuronal regulation and behavioral photoentrainment. Our results reveal that TASK-3 is needed to adapt to challenging lighting conditions, such as those experienced through seasonal changes and jet lag. From our investigations this appears to be very distinct from pathways that drive acute, ‘one-off’ adjustments in clock phase, in response to single pulses of light. These findings provide crucial information on the intricate pathways linking clock output to behavioral adaptation to light-dark cycles.
This paper makes the case for implementing an internal governance framework for sharing materials and data in stem cell research consortia. A governance framework can facilitate a transparent and accountable system while building trust among partner institutions. However, avoiding excessive bureaucracy is essential. The development and implementation of a governance framework for materials and data access in the Stem cells for Biological Assays of Novel drugs and prediCtive toxiCology (StemBANCC) consortium is presented as a practical example. The StemBANCC project is a multi-partner European research consortium, which aims to build a resource of 1,500 well characterised induced pluripotent stem cell (iPSC) lines for in vitro disease modelling and toxicology studies. The project governance framework was developed in two stages. A small working group identified key components of a framework and translated the project legal agreements into a draft policy document. The second phase allowed input from all consortium partners to shape the iterative development of a final policy document that could be agreed by all parties. Careful time management strategies were needed to manage the duration of this component. This part of the process also served as an exploratory space where different options could be proposed, potential gaps in planning identified, and project co-ordination activities specified.
This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways.We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed.Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10-17 , odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 × 10-17 , OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10-8 , OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 × 10-8 , OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache.We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193-202.
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