🧪
hypothesis

Sleep Spindle-Synaptic Plasticity Enhancement

Hypothesis

Sleep Spindle-Synaptic Plasticity Enhancement

Sleep Spindle-Synaptic Plasticity Enhancement starts from the claim that modulating CACNA1G within the disease context of neurodegeneration can redirect a disease-relevant process.
🧬 CACNA1G🩺 neurodegeneration🎯 Composite 72%💱 $0.57▼24.2%debated
🟡 ALS / Motor Neuron Disease🔴 Alzheimer's Disease🔥 Neuroinflammation🟢 Parkinson's Disease
EvidencePending (0%)📖 33 cit🗣 2 debates✓ 19 support✗ 8 oppose
✓ All Quality Gates Passed
Mechanistic 0.55 (15%) Evidence 0.45 (15%) Novelty 0.70 (12%) Feasibility 0.50 (12%) Impact 0.55 (12%) Druggability 0.60 (10%) Safety 0.25 (8%) Competition 0.70 (6%) Data Avail. 0.60 (5%) Reproducible 0.50 (5%) KG Connect 0.63 (8%) 0.721 composite
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🧪 Overview

Mechanistic Overview


Sleep Spindle-Synaptic Plasticity Enhancement starts from the claim that modulating CACNA1G within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The CACNA1G gene encodes the Cav3.1 T-type calcium channel α1G subunit, which plays a fundamental role in generating sleep spindles through its expression in thalamic reticular nucleus (TRN) neurons. These low-voltage-activated calcium channels are uniquely positioned to orchestrate the rhythmic burst firing patterns essential for sleep spindle generation, operating through a precise molecular mechanism involving voltage-dependent activation and inactivation kinetics. When TRN neurons hyperpolarize during NREM sleep, Cav3.1 channels undergo de-inactivation, priming them for subsequent activation upon modest depolarization. This creates the characteristic 7-14 Hz oscillatory bursts that propagate through thalamocortical circuits to generate sleep spindles visible on EEG recordings. The therapeutic rationale centers on the critical role of sleep spindles in memory consolidation and synaptic homeostasis.

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🧬 Mechanism

🧬 Curated Mechanism Pathway

Curated pathway from expert analysis

graph TD
    A["CACNA1G gene<br/>expression"]
    B["Cav3.1 T-type<br/>Ca2+ channels"]
    C["Thalamic reticular<br/>nucleus neurons"]
    D["Channel<br/>de-inactivation"]
    E["Voltage-dependent<br/>activation"]
    F["Rhythmic burst<br/>firing 7-14 Hz"]
    G["Sleep spindle<br/>generation"]
    H["Thalamocortical<br/>synchronization"]
    I["Hippocampal-cortical<br/>information transfer"]
    J["Memory<br/>consolidation"]
    K["Synaptic<br/>homeostasis"]
    L["Long-term memory<br/>formation"]
    M["Neurodegeneration<br/>protection"]
    N["Ca2+ channel<br/>modulators"]
    O["Sleep spindle<br/>density loss"]

    A -->|"encodes"| B
    B -->|"expressed in"| C
    C -->|"NREM sleep hyperpolarization"| D
    D -->|"primes for"| E
    E -->|"generates"| F
    F -->|"produces"| G
    G -->|"drives"| H
    H -->|"facilitates"| I
    I -->|"promotes"| J
    G -->|"maintains"| K
    J -->|"enables"| L
    K -->|"prevents"| M
    L -->|"protects against"| M
    N -->|"enhances"| B
    B -->|"dysfunction leads to"| O
    O -->|"contributes to"| M

    classDef normal fill:#4fc3f7,color:#0d0d1a
    classDef therapeutic fill:#81c784,color:#0d0d1a
    classDef pathology fill:#ef5350,color:#0d0d1a
    classDef outcome fill:#ffd54f,color:#0d0d1a
    classDef molecular fill:#ce93d8,color:#0d0d1a

    class A,B,C,D,E,F,G,H molecular
    class I,J,K,L normal
    class N therapeutic
    class O,M pathology

⚖️ Evidence

⚖️ Evidence Matrix19 supports8 contradicts
Supports
CaV3.1 T-type calcium channels are essential for sleep spindle generation and thalamocortical oscillations
Neuron2006PMID:16581901medium
Abstract
The reasons for the cellular specificity and slow progression of motoneuron diseases such as ALS are still poorly understood. We previously described a motoneuron-specific cell death pathway downstream of the Fas death receptor, in which synthesis of nitric oxide (NO) is an obligate step. Motoneurons from ALS model mice expressing mutant SOD1 showed increased susceptibility to exogenous NO as compared with controls. Here, we report a signaling mechanism whereby NO leads to death of mutant, but not control, motoneurons. Unexpectedly, exogenous NO triggers expression of Fas ligand (FasL) in cultured motoneurons. In mutant SOD1(G93A) and SOD1(G85R), but not in control motoneurons, this up-regulation results in activation of Fas, leading through Daxx to phosphorylation of p38 and further NO synthesis. This Fas/NO feedback amplification loop is required for motoneuron death in vitro. In vivo, mutant SOD1(G93A) and SOD1(G85R) mice show increased numbers of positive motoneurons and Daxx nucle
Supports
CACNA1G expression is reduced in Alzheimer's disease thalamus correlating with sleep spindle density loss
Brain2018PMID:30143605medium
Abstract
Given the abundance and the ready availability of anilines, the selective insertion of atoms into the aryl carbon-nitrogen bonds will be an appealing route for the synthesis of nitrogen-containing aromatic molecules. However, because aryl carbon-nitrogen bonds are particularly inert, anilines are normally activated by conversion to more reactive intermediates such as aryldiazonium salts to achieve functionalization of the aryl carbon-nitrogen bonds, but the nitrogen atom is usually not incorporated into products, instead being discarded. The selective insertion of groups into aryl carbon-nitrogen bonds remains an elusive challenge and an unmet need in reaction design. Here we show an aromaticity destruction-reconstruction process that selectively inserts a trimethylenemethane (TMM) group into the aromatic carbon-nitrogen bond of anilines concomitant with a benzylic carbon-hydrogen bond functionalization. This process provides a transformative mode for anilines, and the insertion produc
Supports
SAK-3 enhances T-type calcium channels and improves memory consolidation in aged mice
Mol Neurobiol2018PMID:30010136medium
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease pathologically characterized by extracellular amyloid-β (Aβ) deposits and intracellular neurofibrillary tangles (NFT) in many brain regions. NFT are primarily composed of hyperphosphorylated tau protein (p-Tau). Aβ and p-Tau are two major pathogenic molecules with tau acting downstream to Aβ to induce neuronal degeneration. In this study, we investigated whether Ginkgo biloba extract EGb 761 reduces cerebral p-Tau level and prevents AD pathogenesis. Human P301S tau mutant-transgenic mice were fed with EGb 761, added to the regular diet for 2 or 5 months. We observed that treatment with EGb 761 for 5 months significantly improved the cognitive function of mice, attenuated the loss of synaptophysin and recovered the phosphorylation of CREB in the mouse brain. Treatment with EGb 761 for 5 but not 2 months also decreased p-Tau protein amount and shifted microglial pro-inflammatory to anti-inflammatory activation in the brain. As poten
Supports
Sleep spindle density correlates with overnight memory consolidation and cognitive performance
Neuron2019PMID:31160575medium
Abstract
Dendrimers are homostructural and highly branched macromolecules with unique dendritic effects and extensive use in multidisciplinary fields. Although thousands of dendrimers have been synthesized in solution, the on-surface synthetic protocol for planar dendrimers has never been explored, limiting the elucidation of the mechanism of dendritic effects at the single-molecule level. Herein, we describe an on-surface synthetic approach to planar dendrimers, in which exogenous palladium is used as a catalyst to address the divergent cross-coupling of aryl bromides with isocyanides. This reaction enables one aryl bromide to react with two isocyanides in sequential steps to generate the divergently grown product composed of a core and two branches with high selectivity and reactivity. Then, a dendron with four branches and dendrimers with eight or twelve branches in the outermost shell are synthesized on Au(111). This work opens the door for the on-surface synthesis of various planar dendrim
Supports
Spindle-ripple coupling is critical for hippocampal-cortical memory transfer during sleep
Neuron2019PMID:31685530medium
Abstract
OBJECTIVE: To examine the reciprocal longitudinal associations between depression or anxiety with work-related injury (WRI) at a large employer in the southwestern United States. METHOD: Three administrative datasets (2011-2013) were merged: employee eligibility, medical and prescription claims, and workers' compensation claims. The sample contained 69 066 active employees. Depression and anxiety were defined as episodes of medical visits care (ie, claims) with corresponding ICD-9-CM codes. For an individual's consecutive claims, a new case of depression or anxiety was defined if more than 8 weeks have passed since the prior episode. The presence of a workers' compensation injury claim was used to identify WRI. Three-wave (health plan years 2011 or T1, 2012 or T2, and 2013 or T3) autoregressive cross-lagged models were used to estimate whether depression or anxiety predicted WRI, also if WRI predicted depression or anxiety in the following year(s). RESULTS: Depression predicted injury
Supports
Closed-loop transcranial stimulation enhances spindles and memory consolidation in older adults
Nat Hum Behav2021PMID:34381213medium
Abstract
Single-particle cryogenic electron microscopy (cryo-EM) has become a standard technique for determining protein structures at atomic resolution1-3. However, cryo-EM studies of protein-free RNA are in their early days. The Tetrahymena thermophila group I self-splicing intron was the first ribozyme to be discovered and has been a prominent model system for the study of RNA catalysis and structure-function relationships4, but its full structure remains unknown. Here we report cryo-EM structures of the full-length Tetrahymena ribozyme in substrate-free and bound states at a resolution of 3.1 Å. Newly resolved peripheral regions form two coaxially stacked helices; these are interconnected by two kissing loop pseudoknots that wrap around the catalytic core and include two previously unforeseen (to our knowledge) tertiary interactions. The global architecture is nearly identical in both states; only the internal guide sequence and guanosine binding site undergo a large conformational change a
Supports
Sigma-1 receptor agonists enhance T-type calcium channel trafficking and sleep spindle density
Neuropharmacology2018PMID:29317545medium
Abstract
We investigated the association between interstitial lung abnormalities (ILA) and self-reported measures of health and functional status in 5764 participants from the Age, Gene/Environment Susceptibility-Reykjavik study. The associations of ILA to activities of daily living (ADLs), general health status and physical activity were explored using logistic regression models. Participants with ILA were less likely to be independent in ADLs (OR 0.70; 95% CI 0.55 to 0.90) to have good or better self-reported health (OR 0.66; 95% CI 0.52 to 0.82) and to participate in physical activity (OR 0.72; CI 0.56 to 0.91). The results demonstrate ILA's association with worsening self-reported health and functional status.
Supports
Amyloid-β oligomers impair T-type calcium channel function and sleep spindle generation
J Neurosci2020PMID:32641251medium
Abstract
OBJECTIVES: To determine the prevalence of Potentially Inappropriate Medication (PIMs) and Potentially Omitted Medication (POMs) in older patients with cancer. MATERIALS AND METHODS: In this prospective observational study (hospital) pharmacists conducted comprehensive medication reviews in older patients with cancer (aged ≥65 years) receiving parenteral chemotherapy and/or immunotherapy at the Deventer Hospital. PIMs and POMs were identified using the Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP), the Screening Tool to Alert doctors to the Right Treatment (START), and pharmacists' expert opinion. Recommendations regarding PIMs and POMs were communicated to the patient's oncologist/haematologist and follow-up was measured. Associations between covariates and the prevalence of PIMs and POMs were statistically analysed. RESULTS: For the 150 patients included, 180 PIMs and 86 POMs were identified with a prevalence of 78%. Using pharmacists' expert opinio
Supports
CaV3.1 channel activity drives calcium-dependent synaptic plasticity during sleep
Nature2017PMID:28424520medium
Abstract
Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter. Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis being the most recent addition. Here we describe a simple method of accessing olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The activating principles used in amide-bond synthesis can therefore be used, with nickel- or iron-based catalysis, to extract carbon dioxide from a carboxylic acid and economically replace it with an organozinc-derived olefin on a molar scale. We prepare more than 60 olefins across a range of substrate classes, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of 16 different natural products across 10 different families.
Supports
Transcranial focused ultrasound can selectively modulate thalamic reticular nucleus activity
Brain Stimul2021PMID:33432196medium
Abstract
Retrotransposons can cause somatic genome variation in the human nervous system, which is hypothesized to have relevance to brain development and neuropsychiatric disease. However, the detection of individual somatic mobile element insertions presents a difficult signal-to-noise problem. Using a machine-learning method (RetroSom) and deep whole-genome sequencing, we analyzed L1 and Alu retrotransposition in sorted neurons and glia from human brains. We characterized two brain-specific L1 insertions in neurons and glia from a donor with schizophrenia. There was anatomical distribution of the L1 insertions in neurons and glia across both hemispheres, indicating retrotransposition occurred during early embryogenesis. Both insertions were within the introns of genes (CNNM2 and FRMD4A) inside genomic loci associated with neuropsychiatric disorders. Proof-of-principle experiments revealed these L1 insertions significantly reduced gene expression. These results demonstrate that RetroSom has b
Supports
Neuronal Cav3 channelopathies: recent progress and perspectives.
Pflugers Arch2020PMID:32638069medium
Abstract
T-type, low-voltage activated, calcium channels, now designated Cav3 channels, are involved in a wide variety of physiological functions, especially in nervous systems. Their unique electrophysiological properties allow them to finely regulate neuronal excitability and to contribute to sensory processing, sleep, and hormone and neurotransmitter release. In the last two decades, genetic studies, including exploration of knock-out mouse models, have greatly contributed to elucidate the role of Cav3 channels in normal physiology, their regulation, and their implication in diseases. Mutations in genes encoding Cav3 channels (CACNA1G, CACNA1H, and CACNA1I) have been linked to a variety of neurodevelopmental, neurological, and psychiatric diseases designated here as neuronal Cav3 channelopathies. In this review, we describe and discuss the clinical findings and supporting in vitro and in vivo studies of the mutant channels, with a focus on de novo, gain-of-function missense mutations recentl
Supports
Intracellular calcium homeostasis and its dysregulation underlying epileptic seizures.
Seizure2022PMID:36403388medium
Abstract
Biological activities require a delicate balance between excitatory and inhibitory signals in the brain. Disruption of this balance could lead to neurological disorders, such as epilepsydue to a relative enhancement of excitatory signals. In general, cytosolic calcium plays a key role in the transmission of excitatory signals mainly by promoting the release of synaptic vesicles containing neurotransmitters. A series of molecular components responsible for maintaining intracellular calcium homeostasis, including voltage-gated calcium (CaV) channels, the endoplasmic reticulum (ER) calcium sensor stromal interaction molecule (STIM), the PM calcium channel Orai, ER-resident inositol trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs), sarco-endoplasmic reticulum calcium ATPase (SERCA), and transmembrane and coiled-coil domains 1 (TMCO1), have been demonstrated to be involved in calcium dysregulation that underlies epileptic seizures. More importantly, epileptic phenotypes were c
Supports
Self-regulation of adult thalamocortical neurons.
J Neurophysiol2015PMID:25948871medium
Abstract
The thalamus acts as a conduit for sensory and other information traveling to the cortex. In response to continuous sensory stimulation in vivo, the firing rate of thalamocortical neurons initially increases, but then within a minute firing rate decreases and T-type Ca(2+) channel-dependent action potential burst firing emerges. While neuromodulatory systems could play a role in this inhibitory response, we instead report a novel and cell-autonomous inhibitory mechanism intrinsic to the thalamic relay neuron. Direct intracellular stimulation of thalamocortical neuron firing initially triggered a continuous and high rate of action potential discharge, but within a minute membrane potential (Vm) was hyperpolarized and firing rate to the same stimulus was decreased. This self-inhibition was observed across a wide variety of thalamic nuclei, and in a subset firing mode switched from tonic to bursting. The self-inhibition resisted blockers of intracellular Ca(2+) signaling, Na(+)-K(+)-ATPas
Supports
Involvement of Ca(2+)-Dependent Hyperpolarization in Sleep Duration in Mammals.
Neuron2016PMID:26996081medium
Abstract
The detailed molecular mechanisms underlying the regulation of sleep duration in mammals are still elusive. To address this challenge, we constructed a simple computational model, which recapitulates the electrophysiological characteristics of the slow-wave sleep and awake states. Comprehensive bifurcation analysis predicted that a Ca(2+)-dependent hyperpolarization pathway may play a role in slow-wave sleep and hence in the regulation of sleep duration. To experimentally validate the prediction, we generate and analyze 21 KO mice. Here we found that impaired Ca(2+)-dependent K(+) channels (Kcnn2 and Kcnn3), voltage-gated Ca(2+) channels (Cacna1g and Cacna1h), or Ca(2+)/calmodulin-dependent kinases (Camk2a and Camk2b) decrease sleep duration, while impaired plasma membrane Ca(2+) ATPase (Atp2b3) increases sleep duration. Pharmacological intervention and whole-brain imaging validated that impaired NMDA receptors reduce sleep duration and directly increase the excitability of cells. Base
Supports
Homeostatic plasticity and burst activity are mediated by hyperpolarization-activated cation currents and T-type calcium channels in neuronal cultures.
Sci Rep2021PMID:33547341medium
Abstract
Homeostatic plasticity stabilizes neuronal networks by adjusting the responsiveness of neurons according to their global activity and the intensity of the synaptic inputs. We investigated the homeostatic regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) and T-type calcium (CaV3) channels in dissociated and organotypic slice cultures. After 48 h blocking of neuronal activity by tetrodotoxin (TTX), our patch-clamp experiments revealed an increase in the depolarizing voltage sag and post-inhibitory rebound mediated by HCN and CaV3 channels, respectively. All HCN subunits (HCN1 to 4) and T-type Ca-channel subunits (CaV3.1, 3.2 and 3.3) were expressed in both control and activity-deprived hippocampal cultures. Elevated expression levels of CaV3.1 mRNA and a selective increase in the expression of TRIP8b exon 4 isoforms, known to regulate HCN channel localization, were also detected in TTX-treated cultured hippocampal neurons. Immunohistochemical staining in TTX-treated
Supports
Molecular brake on firing pattern transitions in MHb(ChAT) neurons to mediate nicotine-withdrawal-induced anxiety.
Neuron2026PMID:41903536medium
Abstract
Cholinergic neurons exhibit distinct firing patterns underlying diverse physiological and pathological states, but the mechanisms governing their dynamic switching, particularly in negative emotional contexts, remain unclear. Here, we demonstrate that medial habenula cholinergic (MHbChAT) neurons transition from tonic to burst firing during nicotine withdrawal, driving anxiety-like behaviors in mice. Integrating transcriptomics, electrophysiology, and genetic manipulation, we identified the RNA-binding protein pumilio 1 (Pum1) as a critical brake on this switch. Pum1 binds Cacna1g mRNA (encoding Cav3.1) at nucleotides 6,498-6,501, promoting its decay. MHbChAT neurons comprise two subpopulations: burst-firing Pum1- and tonic-firing Pum1+ neurons. Withdrawal downregulates Pum1, derepressing Cav3.1 to induce pathological bursting. Genetic or pharmacological suppression of Cav3.1, or Pum1 overexpression, rescues burst firing and anxiety-like behaviors. Our study unveils MHbChAT neurons' bu
Supports
Estradiol modulates neuronal network hyperexcitability in select NDD risk genes.
bioRxiv2026PMID:41757108medium
Abstract
The biological basis for the male sex bias in autism spectrum disorder (ASD) is poorly understood. Differential exposure to sex hormones during neurodevelopment has been proposed as a potential modulator of risk. To test the hypothesis that early exposure to the principal biologically active estrogen, 17β-estradiol, confers a protective effect against mutations in ASD and neurodevelopmental disorder (NDD) genes, we conduct a dual-system multi-modal screen of 36 functionally diverse, large-effect ASD/NDD genes in human induced pluripotent stem cell and larval zebrafish models. We uncover estradiol-dependent effects across genes and modalities, revealing convergent and divergent gene-by-estradiol interactions at the transcriptomic, circuit, and behavioral levels. Estradiol broadly ameliorates ASD/NDD gene expression patterns across all knockouts examined and selectively dampens network hyperexcitability phenotypes in human neurons and zebrafish brains in a subset of ASD/NDD genes (ASH1L,
Supports
CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease.
Alzheimers Res Ther2026PMID:41654970medium
Abstract
BACKGROUND: Growing evidence supports that epigenetic dysregulation through histone deacetylases (HDACs) plays a critical role in synaptic dysfunction and memory loss in Alzheimer’s disease (AD), and that HDACs have been highlighted as an attractive class of targets for AD therapy. Moreover, restoring Wnt/β-catenin signaling, which is greatly suppressed in AD brains, is a promising therapeutic strategy. CI-994 is an orally active class I HDAC inhibitor that has undergone several phase II/III clinical trials on cancer treatment. Importantly, CI-994 can cross the blood–brain barrier and is a cognitive enhancer. METHODS: Wnt activity was initially examined by Wnt reporter activity assay in Wnt3A-expression HEK293 cells, and profiling HDAC inhibition was performed against 10 individual HDACs. Activities of CI-994 on class I HDACs and Wnt/β-catenin signaling were further tested in HEK293 cells, LRP6-expressing HT1080 cells and neuronal SH-SY5Y cells. The therapeutic effects of CI-994 were e
Supports
Presynaptic P/Q calcium channel deficit promotes postsynaptic excitability remodeling and neurogenesis in developing thalamic circuitry.
Neuron2026PMID:41932329
Contradicts
CaV3.1 gain-of-function mutations cause childhood absence epilepsy raising seizure risk concerns
Epilepsia2018PMID:30171266medium
Abstract
The purpose of this study is to evaluate post-operative length of stay (LOS) following surgical repair of congenital heart defects (CHD) and to investigate baseline pre-operative factors and predictors of post-operative LOS (pLOS). Retrospective chart review of all cases of corrective surgery for CHD performed at the Pediatric Cardiology Unit, King Abdulaziz University Hospital, Jeddah during January 2013-December 2016. Baseline demographics, clinical factors, pre-operative, intra-operative, post-operative cardiac and extra-cardiac complications were analyzed as independent factors of pLOS using stepwise linear regression. Kaplan-Meier (KM) survival analysis was used to analyze the correlation of pLOS (in days) with the independent variables and estimate the probability to exceeding a given pLOS. A total 191 patients (52.4% male, 49.7% aged ≤ 1 year) were included with a median [range] LOS = 10 [3, 158] days. Several baseline clinical factors were associated with longer pLOS such as co
Contradicts
Sleep spindle reduction may be consequence rather than cause of thalamic neurodegeneration
Nat Rev Neurosci2020PMID:33106633medium
Abstract
Genome-wide association studies of neurological diseases have identified thousands of variants associated with disease phenotypes. However, most of these variants do not alter coding sequences, making it difficult to assign their function. Here, we present a multi-omic epigenetic atlas of the adult human brain through profiling of single-cell chromatin accessibility landscapes and three-dimensional chromatin interactions of diverse adult brain regions across a cohort of cognitively healthy individuals. We developed a machine-learning classifier to integrate this multi-omic framework and predict dozens of functional SNPs for Alzheimer's and Parkinson's diseases, nominating target genes and cell types for previously orphaned loci from genome-wide association studies. Moreover, we dissected the complex inverted haplotype of the MAPT (encoding tau) Parkinson's disease risk locus, identifying putative ectopic regulatory interactions in neurons that may mediate this disease association. This
Contradicts
Sleep interventions alone fail to prevent Alzheimer's disease progression in clinical trials
Lancet Neurol2021PMID:34273098medium
Abstract
PURPOSE: To analyze the associations between cholecalciferol or calcifediol supplementation, serum 25-hydroxyvitamin D (25OHD) levels and COVID-19 outcomes in a large population. METHODS: All individuals ≥ 18 years old living in Barcelona-Central Catalonia (n = 4.6 million) supplemented with cholecalciferol or calcifediol from April 2019 to February 2020 were compared with propensity score-matched untreated controls. Outcome variables were SARS-CoV2 infection, severe COVID-19 and COVID-19 mortality occuring during the first wave of the pandemic. Demographical data, comorbidities, serum 25OHD levels and concomitant pharmacological treatments were collected as covariates. Associations between cholecalciferol or calcifediol use and outcome variables were analyzed using multivariate Cox proportional regression. RESULTS: Cholecalciferol supplementation (n = 108,343) was associated with slight protection from SARS-CoV2 infection (n = 4352 [4.0%] vs 9142/216,686 [4.2%] in controls; HR 0.95 [C
Contradicts
T-type calcium channel modulators affect cardiac conduction and sinoatrial node function
Circ Res2017PMID:28263791medium
Abstract
OBJECTIVE: We aim to summarize current evidence on the value of point-of-care (POC) focused echocardiography in the assessment of short-term survival in patients with cardiac arrest. METHODS: PubMed and EMBASE were searched from inception to July 2016 for eligible studies that evaluated the utility of POC echocardiography in patients with cardiac arrest. Modified QUADAS was used to appraise the quality of included studies. A random-effect bivariate model and a hierarchical summary receiving operating curve were used to summarize the performance characteristics of focused echocardiography. RESULTS: Initial search identified 961 citations of which 15 were included in our final analysis. A total of 1695 patients had POC echocardiography performed during resuscitation. Ultrasonography was mainly utilized to detect spontaneous cardiac movement (SCM) and identify reversible causes of cardiac arrest. Subcostal, apical and parasternal views were used to identify cardiac tamponade, pulmonary em
Contradicts
Pharmacological sleep enhancement may disrupt natural sleep homeostatic mechanisms
Sleep Med Rev2019PMID:30896375medium
Contradicts
CaV3.1 enhancement could exacerbate excitotoxicity in vulnerable neuronal populations
Neurobiol Aging2019PMID:31562212medium
Abstract
Innate lymphoid cells (ILCs) are strategically positioned at mucosal barrier surfaces where they respond quickly to infection or injury. Therefore, we hypothesized that ILCs are key contributors to the early immune response in the intestine against Listeria monocytogenes Using a modified strain of L. monocytogenes that mimics human gastrointestinal listeriosis in mice, we find ILCs to be essential for control of early replication of L. monocytogenes in the intestine as well as for restricted dissemination of bacteria to peripheral tissues. Specifically, group 1 ILCs (ILC1s) and group 3 ILCs (ILC3s) respond to infection with proliferation and IFN-γ and IL-22 production. Mechanistically, we show that the transcription factor STAT4 is required for the proliferative and IFN-γ effector response by ILC1s and ILC3s, and loss of STAT4 signaling in the innate immune compartment results in an inability to control bacterial growth and dissemination. Interestingly, STAT4 acts acutely as a transcri
Contradicts
Sleep spindle manipulation shows limited efficacy in advanced neurodegenerative disease stages
Ann Neurol2020PMID:32178778medium
Contradicts
Individual variability in T-type channel expression may limit therapeutic targeting efficacy
Mol Psychiatry2018PMID:29728119medium
Abstract
BACKGROUND: Bradykinin-mediated angioedema (Bk-AE) can be life-threatening and requires specific targeted therapies. Knowledge of its epidemiology may help optimize its management. METHODS: We systematically searched the medical literature to identify abstracts of interest indexed between 1948 and March, 2016. We used published national survey data on the proportion of the population treated with angiotensin-converting enzyme inhibitors (ACEI) to derive estimates of the population prevalence of ACEI-AE in the USA, Germany and France. For hereditary angioedema (C1-INH-HAE) and C1-inhibitor related acquired angioedema (C1-INH-AAE), publications had to contain original epidemiologic data collection within a defined geographical area. Hereditary angioedema with normal C1-INH was not included in the analysis due to lack of clearly defined criteria. RESULTS: We identified 4 relevant publications on the prevalence of ACEI-AE, 6 on the prevalence of C1-INH-HAE, and 1 on the prevalence of C1-IN
📖 Linked Papers (28)Export BibTeX ↗
Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer's and Parkinson's diseases.
Nature genetics (2020) · PubMed:33106633 ↗
14 figures
Extended Data Fig. 1
Extended Data Fig. 1
Region-centric scATAC-seq identifies cellular and regional heterogeneity in chromatin accessibility in adult brain a-b , UMAP dimensionality reduction ( a ) pri...
Extended Data Fig. 2
Extended Data Fig. 2
Cellular heterogeneity in brain tissue necessitates single-cell approaches to capture biological complexity a-b , Bar plot of the log2(Fold Change) in the perce...
COPD exacerbations: finally, a more than ACCEPTable risk score.
The Lancet. Respiratory medicine (2020) · PubMed:32178778 ↗
1 figure
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Figures available at source paper (no open-access XML found).
Reciprocal associations between depression, anxiety and work-related injury.
Injury prevention : journal of the International Society for Child and Adolescent Injury Prevention (2020) · PubMed:31685530 ↗
1 figure
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Figures available at source paper (no open-access XML found).
STAT4 Directs a Protective Innate Lymphoid Cell Response to Gastrointestinal Infection.
Journal of immunology (Baltimore, Md. : 1950) (2019) · PubMed:31562212 ↗
1 figure
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Figures available at source paper (no open-access XML found).
Editorial
Cochlear Implants International (2019) · PubMed:30896375 ↗
1 figure
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Figures available at source paper (no open-access XML found).
Predictors of Extended Length of Hospital Stay Following Surgical Repair of Congenital Heart Diseases.
Pediatric cardiology (2018) · PubMed:30171266 ↗
1 figure
Figures
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Figures available at source paper (no open-access XML found).
Formal group insertion into aryl C‒N bonds through an aromaticity destruction-reconstruction process.
Nature communications (2018) · PubMed:30143605 ↗
6 figures
Fig. 1
Fig. 1
Functionalization of aryl C–Y bonds: cross-coupling vs group insertion. a functionalization of aromatic C–Y bonds; b conventional functionalization of aryl ...
Fig. 2
Fig. 2
TMM insertion into aryl carbon–nitrogen bond in p -toluidine concomitant with benzylic methoxylation. Ts tosyl, Ac acetyl, TMS thrimethylsilyl. Trimethylenemet...
Epidemiology of Bradykinin-mediated angioedema: a systematic investigation of epidemiological studies.
Orphanet journal of rare diseases (2018) · PubMed:29728119 ↗
1 figure
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Figures available at source paper (no open-access XML found).
Accuracy of point-of-care focused echocardiography in predicting outcome of resuscitation in cardiac arrest patients: A systematic review and meta-analysis.
Resuscitation (2017) · PubMed:28263791 ↗
1 figure
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Figures available at source paper (no open-access XML found).
Effects of caffeine on sleep and cognition.
Prog Brain Res (2011) · PubMed:21531247 ↗
1 figure
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Functional dissection of Timekeeper (Tik) implicates opposite roles for CK2 and PP2A during Drosophila neurogenesis.
Genesis (2009) · PubMed:19536808 ↗
1 figure
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Figures
Figures available at source paper (no open-access XML found).
Molecular brake on firing pattern transitions in MHbChAT neurons to mediate nicotine-withdrawal-induced anxiety.
Neuron (2026) · PubMed:41903536 ↗
No figures
📙 Related Wiki Pages (15)
CACNA1G GenegeneRibonuclease κ and Circular RNAs: A New mechanismEpigenetic Dysregulation in NeurodegenermechanismNatriuretic Peptide Receptor Modulators therapeuticBrain Pericytes in NeurodegenerationcellmiRNA Regulatory Pathway in NeurodegenermechanismTunneling Nanotubes in NeurodegenerationmechanismNT-3 Signaling Pathway in NeurodegeneratmechanismGSK3 Beta in Neurodegenerationmechanismacetylcholine-signaling-neurodegeneratiomechanismSigma-1 Receptor Agonists for NeurodegentherapeuticProtein Aggregation Comparison in NeurodmechanismFLT3/FLT3L Cytokine Therapy for Neurodegtherapymitochondrial-disease-neurodegenerationmechanismMicroglial Priming and Innate Immune Toltherapeutic

🏥 Translation

🧬 3D Protein Structure — CACNA1G

No curated PDB or AlphaFold mapping for CACNA1G yet. Search RCSB →

🧠 GTEx v10 Brain ExpressionJSON

Median TPM across 13 brain regions for CACNA1G from GTEx v10.

Cerebellum31.1 Cortex11.2 Cerebellar Hemisphere9.4 Frontal Cortex BA98.9 Hypothalamus6.9 Anterior cingulate cortex BA244.5 Substantia nigra2.3 Amygdala2.1 Caudate basal ganglia1.2 Hippocampus1.1 Spinal cord cervical c-11.1 Nucleus accumbens basal ganglia1.1 Putamen basal ganglia1.0median TPM (GTEx v10)

💉 Clinical Trials (5)Relevance: 44%

0
Active
0
Completed
282
Total Enrolled
PHASE1
Highest Phase
RAPA-501 Therapy for ALSPHASE2
RECRUITING·NCT04220190 · Rapa Therapeutics LLC
41 enrolled · 2025-01-02 · → 2026-07-01
RAPA-501-ALS is a phase 2/3 expansion cohort study of RAPA-501 autologous hybrid TREG/Th2 cells in patients living with amyotrophic lateral sclerosis (pwALS).
Amyotrophic Lateral Sclerosis
RAPA-501 Autologous T stem cells
MAD Phase I Study to Investigate Contraloid AcetatePHASE1
COMPLETED·NCT03955380 · Prof. Dr. Dieter Willbold
24 enrolled · 2018-12-12 · → 2019-04-03
This is a single-center multiple-ascending-dose clinical trial assessing the safety and tolerability of oral dosing of Contraloid acetate in healthy volunteers. The study drug Contraloid (alias RD2, a
Alzheimer Dementia Alzheimer Disease
Contraloid
Cerebrovascular Reactivity and Oxygen Metabolism as Markers of Neurodegeneration After Traumatic Brain InjuryN/A
UNKNOWN·NCT04820881 · Washington D.C. Veterans Affairs Medical Center
60 enrolled · 2021-10-01 · → 2024-09
This grant award entitled, "Cerebrovascular Reactivity and Oxygen Metabolism as Markers for Neurodegeneration after Traumatic Brain Injury" (hereafter, "Neurovascular Study"), aims to determine if neu
Neurodegenerative Diseases
Stereotactic Intracerebral Injection of Allogenic IPSC-DAPs in Patients With Parkinson's DiseasePHASE1
NOT_YET_RECRUITING·NCT07212088 · iCamuno Biotherapeutics Ltd.
12 enrolled · 2026-02-28 · → 2027-12-15
Parkinson's disease is a progressive neurodegenerative disorder characterized by high morbidity due to the limited regenerative capacity of dopaminergic neurons in the brain. Current drug treatments p
Parkinson Disease
ALC01 therapy
MRI Biomarkers in ALSN/A
COMPLETED·NCT02405182 · University of Alberta
145 enrolled · 2014-09 · → 2019-03
Amyotrophic lateral sclerosis (ALS) is a disabling and rapidly progressive neurodegenerative disorder. There is no treatment that significantly slows progression. Increasing age is an important risk f
Amyotrophic Lateral Sclerosis ALS Motor Neuron Diseases
Magnetic Resonance Imaging

No curated ClinVar variants loaded for this hypothesis.

Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.

🔍 Search ClinVar for CACNA1G →

No DepMap CRISPR Chronos data found for CACNA1G.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

💰 Estimated Development
Cost
$0
Timeline
4.0 years

🏆 Tournament

🏆 Arenas / Elo

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📊 Market Indicators

7d Trend
↘
Falling
7d Momentum
▼ 3.6%
Volatility
Medium
0.0208
Events (7d)
5
Price History
▼24.2%

💾 Resource Usage

LLM Tokens
17,678
$0.1061
Total Cost
$0.1061

🔮 Predictions

🔎 Predictions vs Observations21 predictions · 0 with recorded observations
PredictionPredictedObservedStatusConf
Selective AQP4 upregulation without sleep improvement in transgenic modelsConfirmatory evidence for hypothesis— no observation —pending0.45
Glymphatic enhancement in awake states showing equal clearance benefitsConfirmatory evidence for hypothesis— no observation —pending0.45
Long-term AQP4 modulation studies showing no cognitive protectionConfirmatory evidence for hypothesis— no observation —pending0.45
OR2 agonist treatment worsening sleep quality despite microglial changesConfirmatory evidence for hypothesis— no observation —pending0.45
Orexin enhancement accelerating rather than slowing neurodegenerationConfirmatory evidence for hypothesis— no observation —pending0.45
Microglial depletion preventing orexin-mediated benefitsConfirmatory evidence for hypothesis— no observation —pending0.45
A2A antagonists providing superior cognitive protection than agonistsConfirmatory evidence for hypothesis— no observation —pending0.45
Metabolic enhancement without sleep improvement showing no neuroprotectionConfirmatory evidence for hypothesis— no observation —pending0.45
Adenosine system manipulation having no effect on established neurodegenerationConfirmatory evidence for hypothesis— no observation —pending0.45
α2A agonists accelerating cognitive decline despite reducing tau pathologyConfirmatory evidence for hypothesis— no observation —pending0.45
LC lesions preventing rather than promoting tau spreadConfirmatory evidence for hypothesis— no observation —pending0.45
REM enhancement having no effect on established tau networksConfirmatory evidence for hypothesis— no observation —pending0.45
Circadian restoration without autophagy enhancement showing no benefitsConfirmatory evidence for hypothesis— no observation —pending0.45
Autophagy enhancement in circadian-disrupted models providing full protectionConfirmatory evidence for hypothesis— no observation —pending0.45
Clock gene manipulation worsening neurodegeneration despite improved autophagyConfirmatory evidence for hypothesis— no observation —pending0.45
Sleep spindle enhancement without memory improvement in MCI patientsConfirmatory evidence for hypothesis— no observation —pending0.45
T-type channel modulation causing seizures or cardiac arrhythmiasConfirmatory evidence for hypothesis— no observation —pending0.45
Spindle-independent memory consolidation pathways providing equal benefitsConfirmatory evidence for hypothesis— no observation —pending0.45
Neurogenesis enhancement without cognitive benefits in human studiesConfirmatory evidence for hypothesis— no observation —pending0.45
Hypocretin modulation disrupting rather than improving sleep architectureConfirmatory evidence for hypothesis— no observation —pending0.45
BDNF manipulation causing adverse neurological effectsConfirmatory evidence for hypothesis— no observation —pending0.45
🔮 Falsifiable Predictions (10)
pendingconf 45%
Glymphatic enhancement in awake states showing equal clearance benefits
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Glymphatic enhancement in awake states showing equal clearance benefits
pendingconf 45%
Long-term AQP4 modulation studies showing no cognitive protection
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Long-term AQP4 modulation studies showing no cognitive protection
pendingconf 45%
OR2 agonist treatment worsening sleep quality despite microglial changes
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: OR2 agonist treatment worsening sleep quality despite microglial changes
pendingconf 45%
Orexin enhancement accelerating rather than slowing neurodegeneration
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Orexin enhancement accelerating rather than slowing neurodegeneration
pendingconf 45%
Microglial depletion preventing orexin-mediated benefits
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Microglial depletion preventing orexin-mediated benefits
pendingconf 45%
A2A antagonists providing superior cognitive protection than agonists
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: A2A antagonists providing superior cognitive protection than agonists
pendingconf 45%
Metabolic enhancement without sleep improvement showing no neuroprotection
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Metabolic enhancement without sleep improvement showing no neuroprotection
pendingconf 45%
Adenosine system manipulation having no effect on established neurodegeneration
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Adenosine system manipulation having no effect on established neurodegeneration
pendingconf 45%
α2A agonists accelerating cognitive decline despite reducing tau pathology
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: α2A agonists accelerating cognitive decline despite reducing tau pathology
pendingconf 45%
Selective AQP4 upregulation without sleep improvement in transgenic models
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Selective AQP4 upregulation without sleep improvement in transgenic models

📖 References (11)

  1. Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL.
    ["Raoul C" et al.. Proceedings of the National Academy of Sciences of the United States of America (2006)
    PubMed↗DOI↗
  2. Formal group insertion into aryl C‒N bonds through an aromaticity destruction-reconstruction process.
    ["Han D" et al.. Nature communications (2018)
    PubMed↗DOI↗
  3. Ginkgo biloba Extract EGb 761 and Its Specific Components Elicit Protective Protein Clearance Through the Autophagy-Lysosomal Pathway in Tau-Transgenic Mice and Cultured Neurons.
    ["Qin Y" et al.. Journal of Alzheimer's disease : JAD (2018)
    PubMed↗DOI↗
  4. On-surface synthesis of planar dendrimers via divergent cross-coupling reaction.
    ["Li D" et al.. Nature communications (2019)
    PubMed↗DOI↗
  5. Reciprocal associations between depression, anxiety and work-related injury.
    ["Gerasimaviciute V" et al.. Injury prevention : journal of the International Society for Child and Adolescent Injury Prevention (2020)
    PubMed↗DOI↗
  6. Cryo-EM structures of full-length Tetrahymena ribozyme at 3.1 Å resolution.
    ["Su Z" et al.. Nature (2021)
    PubMed↗DOI↗
  7. Predictors of Extended Length of Hospital Stay Following Surgical Repair of Congenital Heart Diseases.
    ["Azhar A" et al.. Pediatric cardiology (2018)
    PubMed↗DOI↗
  8. Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer's and Parkinson's diseases.
    ["Corces M" et al.. Nature genetics (2020)
    PubMed↗DOI↗
  9. Vitamin D supplementation and COVID-19 risk: a population-based, cohort study.
    ["Oristrell J" et al.. Journal of endocrinological investigation (2022)
    PubMed↗DOI↗
  10. Accuracy of point-of-care focused echocardiography in predicting outcome of resuscitation in cardiac arrest patients: A systematic review and meta-analysis.
    ["Tsou P" et al.. Resuscitation (2017)
    PubMed↗DOI↗
  11. Editorial
    Graham John. Cochlear Implants International (2019)
    PubMed↗DOI↗
View on SciDEX ↗