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BioRxiv : the Preprint Server For... Jun 2023Protein synthesis is a fundamental cellular process in neurons that is essential for synaptic plasticity and memory consolidation. Here, we describe our investigations...
UNLABELLED
Protein synthesis is a fundamental cellular process in neurons that is essential for synaptic plasticity and memory consolidation. Here, we describe our investigations of a neuron- and muscle-specific translation factor, e ukaryotic E longation F actor 1a2 (eEF1A2), which when mutated in patients results in autism, epilepsy, and intellectual disability. We characterize three most common patient mutations, G70S, E122K, and D252H, and demonstrate that all three mutations decrease protein synthesis and elongation rates in HEK293 cells. In mouse cortical neurons, the mutations not only decrease protein synthesis, but also alter neuronal morphology, regardless of endogenous levels of eEF1A2, indicating that the mutations act via a toxic gain of function. We also show that eEF1A2 mutant proteins display increased tRNA binding and decreased actin bundling activity, suggesting that these mutations disrupt neuronal function by decreasing tRNA availability and altering the actin cytoskeleton. More broadly, our findings are consistent with the idea that eEF1A2 acts as a bridge between translation and the actin skeleton, which is essential for proper neuron development and function.
SIGNIFICANCE STATEMENT
E ukaryotic E longation F actor 1A2 (eEF1A2) is a muscle- and neuron-specific translation factor responsible for bringing charge tRNAs to the elongating ribosome. Why neurons express this unique translation factor is unclear; however, it is known that mutations in cause severe drug-resistant epilepsy, autism and neurodevelopmental delay. Here, we characterize the impact of three common disease-causing mutations in and demonstrate that they cause decreased protein synthesis via reduced translation elongation, increased tRNA binding, decreased actin bundling activity, as well as altered neuronal morphology. We posit that eEF1A2 serves as a bridge between translation and the actin cytoskeleton, linking these two processes that are essential for neuronal function and plasticity.
PubMed: 37333416
DOI: 10.1101/2023.06.06.543912 -
Translational Psychiatry May 2014Childhood adversity alters the predisposition to psychiatric disorders later in life. Those with psychiatric conditions and a history of early adversity exhibit a higher... (Review)
Review
Childhood adversity alters the predisposition to psychiatric disorders later in life. Those with psychiatric conditions and a history of early adversity exhibit a higher incidence of treatment resistance compared with individuals with no such history. Modulation of the influence early stress exerts over neurobiology may help to prevent the development of psychiatric disorders in some cases, while attenuating the extent of treatment resistance in those with established psychiatric disorders. This review aims to critically evaluate the ability of behavioural, environmental and pharmacologic interventions to modulate neurobiological changes induced by early stress in animal models. Databases were systematically searched to locate literature relevant to this review. Early adversity was defined as stress that resulted from manipulation of the mother-infant relationship. Analysis was restricted to animal models to enable characterisation of how a given intervention altered specific neurobiological changes induced by early stress. A wide variety of changes in neurobiology due to early stress are amenable to intervention. Behavioural interventions in childhood, exercise in adolescence and administration of epigenetic-modifying drugs throughout life appear to best modulate cellar and behavioural alterations induced by childhood adversity. Other pharmacotherapies, such as endocannabinoid system modulators, anti-inflammatories and antidepressants can also influence these neurobiological and behavioural changes that result from early stress, although findings are less consistent at present and require further investigation. Further work is required to examine the influence that behavioural interventions, exercise and epigenetic-modifying drugs exert over alterations that occur following childhood stress in human studies, before possible translational into clinical practice is possible.
Topics: Animals; Brain; Disease Models, Animal; Mental Disorders; Stress, Psychological
PubMed: 24825729
DOI: 10.1038/tp.2014.31 -
American Journal of Cardiovascular... Jun 2012According to prior analyses, extended-release niacin/laropiprant (ERN/LRPT) consistently reduces low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) and...
BACKGROUND
According to prior analyses, extended-release niacin/laropiprant (ERN/LRPT) consistently reduces low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) and increases high-density lipoprotein cholesterol (HDL-C) levels across a wide range of dyslipidemic patient subgroups.
OBJECTIVES
This analysis examined ERN/LRPT's consistency across four phase III, randomized, double-blind trials in improving other lipid/lipoprotein parameters associated with cardiovascular risk, across several key dyslipidemic patient subgroups.
METHODS
In three of the studies, the randomized population included patients with primary hypercholesterolemia or mixed hyperlipidemia; in the remaining study, the population included patients with type 2 diabetes mellitus. The lipid-altering consistency of ERN/LRPT's efficacy was evaluated versus the pre-defined comparator (placebo or active control) among key subgroups of sex, race (White, non-White), region (US, ex-US), baseline age (<65 years, ≥65 years), use of statin therapy (yes, no), coronary heart disease (yes, no), risk status (low, multiple, high), and type of hyperlipidemia (primary hypercholesterolemia, mixed dyslipidemia), as well as across baseline LDL-C, HDL-C, and TG levels. The consistency of the treatment effects on lipoprotein(a).[Lp(a)], apolipoprotein B (ApoB), non-HDL-C, ApoA1, and ApoB/ApoA1 ratio was evaluated by examining treatment difference estimates of the percentage change from baseline with 95% confidence intervals.
RESULTS
Treatment with ERN/LRPT produced significantly greater improvements in Lp(a), ApoB, non-HDL-C, ApoA1, and ApoB/ApoA1 ratio compared with placebo/active comparator in each study. These effects were generally consistent across key subgroups within each study.
CONCLUSION
ERN/LRPT produced lipid-altering efficacy on the parameters evaluated in four controlled studies; these effects were generally consistent across all examined subgroups. ERN/LRPT represents an effective and reliable therapeutic option for the treatment of dyslipidemia in a wide range of patient types.
CLINICAL TRIAL REGISTRATION
Registered as Clinicaltrials.gov NCT00269204, NCT00269217, NCT00479388, and NCT00485758.
Topics: Aged; Apolipoprotein A-I; Apolipoproteins B; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Double-Blind Method; Dyslipidemias; Female; Humans; Hypolipidemic Agents; Indoles; Lipids; Lipoprotein(a); Male; Niacin; Randomized Controlled Trials as Topic
PubMed: 22500948
DOI: 10.2165/11631530-000000000-00000 -
Frontiers in Psychology 2014Previous research has demonstrated that altered auditory feedback (AAF) disrupts music performance and causes disruptions in both action planning and the perception of...
Previous research has demonstrated that altered auditory feedback (AAF) disrupts music performance and causes disruptions in both action planning and the perception of feedback events. It has been proposed that this disruption occurs because of interference within a shared representation for perception and action (Pfordresher, 2006). Studies reported here address this claim from the standpoint of error monitoring. In Experiment 1 participants performed short melodies on a keyboard while hearing no auditory feedback, normal auditory feedback, or alterations to feedback pitch on some subset of events. Participants overestimated error frequency when AAF was present but not for normal feedback. Experiment 2 introduced a concurrent load task to determine whether error monitoring requires executive resources. Although the concurrent task enhanced the effect of AAF, it did not alter participants' tendency to overestimate errors when AAF was present. A third correlational study addressed whether effects of AAF are reduced for a subset of the population who may lack the kind of perception/action associations that lead to AAF disruption: poor-pitch singers. Effects of manipulations similar to those presented in Experiments 1 and 2 were reduced for these individuals. We propose that these results are consistent with the notion that AAF interference is based on associations between perception and action within a forward internal model of auditory-motor relationships.
PubMed: 25191294
DOI: 10.3389/fpsyg.2014.00914 -
Autophagy 2007Macroautophagy (hereafter referred to as autophagy) is the major degradative pathway of long-lived proteins and organelles that fulfils key functions in cell survival,... (Review)
Review
Macroautophagy (hereafter referred to as autophagy) is the major degradative pathway of long-lived proteins and organelles that fulfils key functions in cell survival, tissue remodeling and tumor suppression. Consistently, alterations in autophagy have been involved in a growing list of pathologies including toxic injury, infections, neurodegeneration, myopathies and cancers. Although critical, the molecular mechanisms that control autophagy remain largely unknown. We have recently exploited the disruption of autophagy by environmental carcinogens as a powerful model to uncover the underlying signaling pathways. Our work published in Cancer Research revealed that the sustained activation of the MAPK ERK pathway by the carcinogen Lindane or the MEK1(+) oncogene alters autophagy selectively at the maturation step resulting in the accumulation of large defective autolysosomes. Consistent with our findings, a similar defect is observed with other common xenobiotics such as dichlorodiphenyltrichloroethane and biphenol A that specifically activate ERK. Conversely, Pentachlorophenol that activates both ERK and p38, fails to induce autophagic vacuolation. In addition, evidence is provided that abrogation of p38 by SB203580 is sufficient to interfere with the normal autophagic maturation step. Altogether, these findings underscore the critical role played by MAPK ERK and p38 in the tight control of the autophagy process at the maturation step.
Topics: Animals; Autophagy; Carcinogens, Environmental; Hexachlorocyclohexane; Humans; Mitogen-Activated Protein Kinases; Models, Biological; Phagosomes; p38 Mitogen-Activated Protein Kinases
PubMed: 17102581
DOI: 10.4161/auto.3424 -
The Journal of Rheumatology. Supplement Nov 2007The early diagnosis and treatment of nascent rheumatoid arthritis (RA) has become a prime objective for rheumatologists and clinicians who care for patients with... (Review)
Review
The early diagnosis and treatment of nascent rheumatoid arthritis (RA) has become a prime objective for rheumatologists and clinicians who care for patients with arthritis. Population-based studies have consistently shown that patients with RA are at substantial risk for progressive joint damage, disability, and increased morbidity and mortality. These inevitable outcomes are closely linked to the consequences of rheumatoid inflammation, which begins early and is progressive in all. At issue is whether early diagnosis, coupled with aggressive therapy, might alter the natural history of this RA. If this "window of opportunity" exists, then outcomes should be substantially altered by delivering the right therapies at the right time. A growing body of evidence has emphasized the consistent clinical and radiographic benefits of early, aggressive treatment of RA. These studies confirm that all therapies - monotherapy, combination disease modifying antirheumatic drugs (DMARD), biologics - work better in early disease than in long-established RA. Earlier identification, referral, and an accurate diagnosis of RA can now be rewarded with highly effective DMARD or biologic therapies. Rheumatologists should rise to the challenge and educate clinicians about this window of opportunity, the potential for remission, and superior clinical responses when patients with early RA or undifferentiated arthritis are referred to and managed by experts in aggressive rheumatologic care.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Clinical Trials as Topic; Early Diagnosis; Humans; Practice Guidelines as Topic; Prognosis; Treatment Outcome
PubMed: 17985417
DOI: No ID Found -
Adipocyte Dec 2020Adipocyte-mediated inflammatory signalling has been proposed to alter adipose physiology in obesity and Type 2 diabetes mellitus. Novel targets for alteration of...
Adipocyte-mediated inflammatory signalling has been proposed to alter adipose physiology in obesity and Type 2 diabetes mellitus. Novel targets for alteration of inflammatory signalling are needed to improve obesity-related outcomes. The γ-secretase enzyme complex has been suggested to play a role both in adipocyte function as well as in immune regulation. We hypothesized that adipocyte-specific γ-secretase inhibition could alter the inflammatory makeup of adipose tissue. We found that genetic blockade of γ-secretase in adipocytes leads to a decrease in (F4/80) expression, as a marker of macrophage presence, in adipose tissue without changes in expression of markers of other inflammatory cell types. To explore the mechanism by which adipocytes can alter macrophage function , fully differentiated 3T3-L1 adipocytes were treated with a γ-secretase inhibitor in the presence of lipopolysaccharide (LPS) and transcription of and (MCP1) were quantified. IL-6 expression and secretion were significantly inhibited by γ-secretase blockade, with little effect on MCP1. Preconditioned media from 3T3-L1 adipocytes treated with a γ-secretase inhibitor also alters macrophage activation but did not affect macrophage translocation . Therefore, γ-secretase inhibition in fully differentiated adipocytes can alter IL-6 signalling to macrophages, consistent with our hypothesis that that γ-secretase is involved in adipocyte-initiated inflammatory signalling cascades.
Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Amyloid Precursor Protein Secretases; Animals; Biomarkers; Cytokines; Inflammation Mediators; Interleukin-6; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Panniculitis; Protease Inhibitors; Signal Transduction
PubMed: 32603641
DOI: 10.1080/21623945.2020.1788235 -
Cancer Research Nov 1978The epidemiological and clinical evidence for various forms of exogenous estrogens altering the risk of neoplasms of the female genital system, breast, and liver are... (Review)
Review
The epidemiological and clinical evidence for various forms of exogenous estrogens altering the risk of neoplasms of the female genital system, breast, and liver are reviewed and evaluated. It is virtually certain that in utero exposure to diethylstilbestrol can cause clear cell adenocarcinomas of the vagina and cervix. There is strong evidence that various estrogens given for treatment of menopausal symptoms can cause endometrial carcinoma and that sequential oral contraceptives probably also do so. Oral contraceptives very probably reduce the risk of both cystic disease and fibroadenoma of the breast and increase the risk of liver cell adenomas. Studies to date do not provide consistent and convincing evidence that any form of exogenous estrogen alters the risk of cancers of the breast or ovary or that oral contraceptives alter the risk of cervical neoplasia or focal nodular hyperplasia of the liver, although recent reports suggest that continued vigilance is warranted. Specific topics requiring further epidemiological investigation are suggested.
Topics: Adenocarcinoma; Adolescent; Adult; Aged; Breast Neoplasms; Carcinoma, Hepatocellular; Contraceptives, Oral; Diethylstilbestrol; Estradiol Congeners; Female; Humans; Liver Neoplasms; Maternal-Fetal Exchange; Middle Aged; Ovarian Neoplasms; Pregnancy; Risk; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Uterine Neoplasms; Vaginal Neoplasms
PubMed: 212185
DOI: No ID Found -
Physiology & Behavior Aug 2012The detrimental effects of steroid-mimics are well known but investigations on non-steroid pharmaceuticals are less common. In addition, most behavioral studies do not...
The detrimental effects of steroid-mimics are well known but investigations on non-steroid pharmaceuticals are less common. In addition, most behavioral studies do not examine the effects at multiple time points. This study examined the effects of fluoxetine, a selective serotonin reuptake inhibitor, on behavior when male Siamese fighting fish encounter female and male dummy conspecifics simultaneously. Thus, how chemical exposure impacts behavioral consistency and whether individuals differ in their sensitivity to exposure was assessed. Overall aggression was reduced after fluoxetine administration while courtship was unaffected. Fluoxetine affected behavioral consistency towards both the male and female, with individuals behaving less consistently to the male and more consistently to the female. In addition, males appeared to differ in their sensitivity to fluoxetine exposure as not all males reduced their aggression after administration. This has important implications for studying the effects of unintended pharmaceutical exposure. Exposure may have evolutionary implications as it may influence both territorial defense and mating success. In sum, these findings demonstrate that pharmaceutical exposure may alter more than just overall level of behavior and stress the importance of examining the effects of exposure on an individual level.
Topics: Aggression; Animals; Antidepressive Agents, Second-Generation; Courtship; Female; Fishes; Fluoxetine; Male; Multivariate Analysis; Sexual Behavior, Animal
PubMed: 22722098
DOI: 10.1016/j.physbeh.2012.06.007 -
Pharmacological Research Aug 2009Marijuana is consistently the most widely used illicit drug among teenagers and most users first experiment it in adolescence. Adolescence is the period between... (Review)
Review
Marijuana is consistently the most widely used illicit drug among teenagers and most users first experiment it in adolescence. Adolescence is the period between childhood and adulthood, encompassing not only reproductive maturation, but also cognitive, emotional and social maturation and is characterized by a brain in transition that differs anatomically and neurochemically from that of the adult. The endocannabinoid system plays an important role in this critical phase for cerebral development, therefore a strong stimulation by the psychoactive component of marijuana, delta-9-tetrahydrocanabinol, that acts through the cannabinoid system, might lead to subtle but lasting neurobiological changes that can affect adult brain functions and behaviour. The literature here summarized, exploiting animal models of cannabis consumption, points to the presence of subtle changes in the adult brain circuits after heavy cannabis consumption in adolescence. These alterations lead to impaired emotional and cognitive performance, enhanced vulnerability for the use of more harmful drugs of abuse, and may represent a risk factor for developing schizophrenia in adulthood. The few studies examining the neurobiological basis of the altered behaviours demonstrate the presence of stable alteration in the endocannabinoid system that can trigger subsequent alteration in synaptic protein and synaptic morphology, thus altering the responsiveness of selected brain areas to different internal and external stimuli. These pre-clinical observations are strengthened by literature in humans where longitudinal studies often support the experimental results. There is an urgent need of multidisciplinary approaches combining behaviour with neurochemical and genetic studies to build a scientific based opinion on the long-lasting consequences of cannabis use in adolescence.
Topics: Adolescent; Adult; Behavior; Brain; Cannabinoids; Cognition Disorders; Humans; Longitudinal Studies; Neurobiology
PubMed: 19559364
DOI: 10.1016/j.phrs.2009.03.006