ANALYSIS OF FACTORS ASSOCIATED WITH FRAILTY SYNDROME IN PATIENTS WITH HEART FAILURE.

OBJECTIVE: Aim: Determination of factors associated with frailty syndrome (FS) in patients with heart failure (HF). PATIENTS AND METHODS: Materials and methods: Consecutive patients hospitalized in the department were assessed for the presence of FS using L. Fried criteria, Edmonton Frail Scale (EFS) and Tilburg Frailty Indicator (TFI). Presence of arterial hypertension, diabetes, obesity, chronic obstructive pulmonary disease (COPD), and heart failure was included in the analysis based on patients' medical history and findings from current hospitalization. Patients were assessed for the presence of depression using Beck's Depression Inventory (BDI). Physical capacity was assessed using NYHA classification. RESULTS: Results: 87 patients (mean age 81.4±6.7; 57 women; 11 HFrEF, mean NYHA 2.36±1.21; 11 HFmrEF, mean NYHA 2.18±1.08; 65 HFpEF mean NYHA 1.94±1.09) were included in the analysis. Multivariable analysis showed significant relationship between FS assessed with EFS and age (ß=0.316, SE=0.08; p=0.0001), arterial hypertension (ß=-0.194, SE=0.08; p=0.0173), COPD (ß=0.176, SE=0.08; p=0.0300) and depression (ß=0.565, SE=0.08; p=0.0000). FS assessed with L. Fried criteria was significantly related to age (ß=0.359, SE=0.09; p= 0.0001), NYHA classification (ß= 0.336, SE=0.09; p=0.0002) and depression (ß=0.297, SE=0.09; p=0.0010). Age (ß=0.251, SE=0.10; p=0.0114) and depression (ß=0.375, SE=0.1; p=0.0002) were significantly related to FS assessed using TFI. In multivariable analysis HF phenotype was not significantly related to FS. CONCLUSION: Conclusions: Age and depression assessed with BDI are related to FS in patients with HF. Arterial hypertension and COPD are linked to FS assessed using EFS, whereas NYHA classification is linked to FS assessed with L. Fried criteria. No statistically significant relationship was found between FS and HF phenotype.

TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study.

PURPOSE: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. METHODS: Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. RESULTS: Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizure-free survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. CONCLUSION: TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.

Cyr61, a matricellular protein, is needed for dendritic arborization of hippocampal neurons.

The shape of the dendritic arbor is one of the criteria of neuron classification and reflects functional specialization of particular classes of neurons. The development of a proper dendritic branching pattern strongly relies on interactions between the extracellular environment and intracellular processes responsible for dendrite growth and stability. We previously showed that mammalian target of rapamycin (mTOR) kinase is crucial for this process. In this work, we performed a screen for modifiers of dendritic growth in hippocampal neurons, the expression of which is potentially regulated by mTOR. As a result, we identified Cyr61, an angiogenic factor with unknown neuronal function, as a novel regulator of dendritic growth, which controls dendritic growth in a ß1-integrin-dependent manner.

Beyond control of protein translation: what we have learned about the non-canonical regulation and function of mammalian target of rapamycin (mTOR).

Mammalian target of rapamycin (mTOR) is a serine-threonine kinase involved in almost every aspect of mammalian cell function. This kinase was initially believed to control protein translation in response to amino acids and trophic factors, and this function has become a canonical role for mTOR. However, mTOR can form two separate protein complexes (mTORCs). Recent advances clearly demonstrate that both mTORCs can respond to various stimuli and change myriad cellular processes. Therefore, our current view of the cellular roles of TORCs has rapidly expanded and cannot be fully explained without appreciating recent findings about the new modes of mTOR regulation and identification of non-canonical effectors of mTOR that contribute to transcription, cytoskeleton dynamics, and membrane trafficking. This review discusses the molecular details of these newly discovered non-canonical functions that allow mTORCs to control the cellular environment at multiple levels. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).

Association between Blood Parameters of Nutritional Status and Functional Status in Extreme Longevity.

BACKGROUND: The relationship between functional and nutritional status in the geriatric population remains an issue of debate and there is a gap in the knowledge regarding this field in long-lived individuals. AIM: The main aim of this study was to assess the association between selected blood parameters of nutritional status and functional status in extreme longevity. METHODS: The inclusion criteria were centenarians above 100 years of age who were examined at their homes, and blood samples were collected. The study group consisted of 170 individuals (25 men and 145 women, median age 100.75 years [100.29-101.58]). RESULTS: Total protein and albumin serum concentration was significantly lower in long-lived individuals with severe functional decline compared to individuals with preserved functional status, p = 0.000001 and p = 0.0000, respectively. Iron serum level was significantly higher in the group with preserved functional status, p = 0.04. Preserved functional status was positively correlated with total protein serum concentration (p = 0.000), albumin concentration (p = 0.000), and iron serum level (p = 0.029). A negative correlation was stated between c-reactive protein (CRP) and functional status (p = 0.032). Univariable logistic regression analysis showed that the functional status of long-lived individuals depends on total protein (OR 2.89, CI 95% [1.67-5.0]) and albumin concentrations (OR 2.34, CI 95% [1.39-3.92]). Multivariable backward stepwise logistic regression analysis showed that a total protein concentration was the only variable independently related to the preserved functional status (OR 3.2, 95% Cl [1.8-5.67]). CONCLUSIONS: In long-lived individuals, the total serum protein and albumin levels are lower in centenarians with severe functional decline, and they correlate with functional status. Total protein serum concentration is the only factor independently related to the preserved functional status in extreme longevity.

Rab11 regulates autophagy at dendritic spines in an mTOR- and NMDA-dependent manner.

Synaptic plasticity is a process that shapes neuronal connections during neurodevelopment and learning and memory. Autophagy is a mechanism that allows the cell to degrade its unnecessary or dysfunctional components. Autophagosomes appear at dendritic spines in response to plasticity-inducing stimuli. Autophagy defects contribute to altered dendritic spine development, autistic-like behavior in mice, and neurological disease. While several studies have explored the involvement of autophagy in synaptic plasticity, the initial steps of the emergence of autophagosomes at the postsynapse remain unknown. Here, we demonstrate a postsynaptic association of autophagy-related protein 9A (Atg9A), known to be involved in the early stages of autophagosome formation, with Rab11, a small GTPase that regulates endosomal trafficking. Rab11 activity was necessary to maintain Atg9A-positive structures at dendritic spines. Inhibition of mTOR increased Rab11 and Atg9A interaction and increased the emergence of LC3 positive vesicles, an autophagosome membrane-associated protein marker, in dendritic spines when coupled to NMDA receptor stimulation. Dendritic spines with newly formed LC3+ vesicles were more resistant to NMDA-induced morphologic change. Rab11 DN overexpression suppressed appearance of LC3+ vesicles. Collectively, these results suggest that initiation of autophagy in dendritic spines depends on neuronal activity and Rab11a-dependent Atg9A interaction that is regulated by mTOR activity.

Mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) control the dendritic arbor morphology of hippocampal neurons.

Dendrites are the main site of information input into neurons. Their development is a multistep process controlled by mammalian target of rapamycin (mTOR) among other proteins. mTOR is a serine/threonine protein kinase that forms two functionally distinct complexes in mammalian cells: mTORC1 and mTORC2. However, the one that contributes to mammalian neuron development remains unknown. This work used short hairpin RNA against Raptor and Rictor, unique components of mTORC1 and mTORC2, respectively, to dissect mTORC involvement in this process. We provide evidence that both mTOR complexes are crucial for the proper dendritic arbor morphology of hippocampal neurons. These two complexes are required for dendritic development both under basal conditions and upon the induction of mTOR-dependent dendritic growth. We also identified Akt as a downstream effector of mTORC2 needed for proper dendritic arbor morphology, the action of which required mTORC1 and p70S6K1.

Dendritic arbor dynamics and stability in health and disease.

Dendritogenesis, a process of dendritic arbor development, is essential for the formation of functional neuronal networks, and in mammals, it begins in early life and continues into adulthood. It is a highly dynamic process in which dendritic branches form and regress until mature connectivity is achieved. Thereafter, dendritic branches are considered stable and do not undergo substantial rearrangements, although several exceptions have been described in the literature. After this long period of relative stability, significant changes in dendritic branching occur when the brain begins to age. Several neurological diseases, occurring both during development and in adulthood, have severe effects on the morphology of dendritic arbors, often associated with intellectual dysfunction. The molecular mechanisms of dendritogenesis are fairly well described. In contrast, knowledge of the molecular mechanisms of dendritic arbor stabilization and pathology­induced instability is still quite incomplete, and several important questions remain unanswered. We describe the dynamic changes during development and adulthood and in different pathologies. Whenever possible, we also provide details on the molecular mechanisms behind dendritic dynamics and stability.

Molecular EPISTOP, a comprehensive multi-omic analysis of blood from Tuberous Sclerosis Complex infants age birth to two years.

We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age. Thirty-nine proteins, metabolites, and genes showed significant differences between age-matched control and TSC infants. Six also showed a progressive difference in expression between control, TSC without epilepsy, and TSC with epilepsy groups. A multivariate approach using enrollment samples identified multiple 3-variable predictors of epilepsy, with the best having a positive predictive value of 0.987. This rich dataset will enable further discovery and analysis of developmental effects, and associations with seizure development in TSC.

CLIP-170 and IQGAP1 cooperatively regulate dendrite morphology.

Dendritic arbors are compartments of neurons dedicated to receiving synaptic inputs. Their shape is an outcome of both the intrinsic genetic program and environmental signals. The microtubules and actin cytoskeleton are both crucial for proper dendritic morphology, but how they interact is unclear. The present study demonstrates that microtubule plus-end tracking protein CLIP-170 and actin-binding protein IQGAP1 regulate dendrite morphology of rat neurons by coordinating the interaction between microtubules and the actin cytoskeleton. Moreover, we show that mTOR kinase interacts with CLIP-170 and is needed for efficient formation of a protein complex containing CLIP-170 and IQGAP1. Dynamic microtubules, CLIP-170, and IQGAP1 are required for proper dendritic arbor morphology and PI3K-mTOR-induced increase in dendritic arbor complexity. Moreover, CLIP-170 and IQGAP1 knockdown modulates dendritic arbor growth via regulation of the actin cytoskeleton. We postulate that mTOR controls dendritic arbor morphology by enhancing cross talk between dynamic microtubules and actin through CLIP-170 and IQGAP1.

Distinct molecular regulation of glycogen synthase kinase-3alpha isozyme controlled by its N-terminal region: functional role in calcium/calpain signaling.

Glycogen synthase kinase-3 (GSK-3) is expressed as two isozymes α and ß. They share high similarity in their catalytic domains but differ in their N- and C-terminal regions, with GSK-3α having an extended glycine-rich N terminus. Here, we undertook live cell imaging combined with molecular and bioinformatic studies to understand the distinct functions of the GSK-3 isozymes focusing on GSK-3α N-terminal region. We found that unlike GSK-3ß, which shuttles between the nucleus and cytoplasm, GSK-3α was excluded from the nucleus. Deletion of the N-terminal region of GSK-3α resulted in nuclear localization, and treatment with leptomycin B resulted in GSK-3α accumulation in the nucleus. GSK-3α rapidly accumulated in the nucleus in response to calcium or serum deprivation, and accumulation was strongly inhibited by the calpain inhibitor calpeptin. This nuclear accumulation was not mediated by cleavage of the N-terminal region or phosphorylation of GSK-3α. Rather, we show that calcium-induced GSK-3α nuclear accumulation was governed by GSK-3α binding with as yet unknown calpain-sensitive protein or proteins; this binding was mediated by the N-terminal region. Bioinformatic and experimental analyses indicated that nuclear exclusion of GSK-3α was likely an exclusive characteristic of mammalian GSK-3α. Finally, we show that nuclear localization of GSK-3α reduced the nuclear pool of ß-catenin and its target cyclin D1. Taken together, these data suggest that the N-terminal region of GSK-3α is responsible for its nuclear exclusion and that binding with a calcium/calpain-sensitive product enables GSK-3α nuclear retention. We further uncovered a novel link between calcium and nuclear GSK-3α-mediated inhibition of the canonical Wnt/ß-catenin pathway.

Developmental plasticity of the dendritic compartment: focus on the cytoskeleton.

Plasticity, the ability to undergo lasting changes in response to a stimulus, is an important attribute of neurons. It allows proper development and underlies learning, memory, and the recovery of the nervous system after severe injuries. Often, an outcome of neuronal plasticity is a structural plasticity manifested as a change of neuronal morphology. In this chapter, we focus on the structural plasticity of dendritic arbors and spines during development. Dendrites receive and compute synaptic inputs from other neurons. The number of dendrites and their branching pattern are strictly correlated with the function of a particular neuron and the geometry of the connections it receives. The development of proper dendritic tree morphology depends on the interplay between genetic programming and extracellular signals. Spines are tiny actin-rich dendritic protrusions that harbor excitatory synapses. No consensus has been reached regarding how dendritic spines form, and several models of spine morphogenesis exist. Nevertheless, most researchers agree that spinogenesis is an important target for structural plasticity. In this chapter, we discuss examples of such plasticity and describe the principles and molecular mechanisms underlying this process, focusing mostly on the regulation of the cytoskeleton during dendrito- and spinogenesis.

Malnutrition in Older Adults-Effect on Falls and Fractures: A Narrative Review.

Malnutrition in older adults impacts health status, increased mortality, and morbidity. Malnutrition may increase the development of geriatric syndromes and contribute to a higher prevalence of falls and osteoporotic fractures that lead to loss of independence and an increased rate of institutionalization. The role of malnutrition in the pathogenesis of other geriatric syndromes seems to be well established. However, the data concerning nutritional interventions are confounding. Moreover, long-term undernutrition seems to be one of the factors that strongly influences the efficacy of interventions. This review outlines the current literature on this topic, and aims to guide physicians to make proper decisions to prevent the vicious cycle of falls, fractures, and their negative outcomes in patients with malnutrition.

Fracture risk in obesity: a narrative review.

While low body mass index (BMI) is a risk factor for fractures, the association between obesity and fracture risk is inconsistent and puzzling. Several studies reported higher fracture risk (FR), and others reported lower FR in obese populations. Our narrative review presents the overall incidence of fractures by anatomic locations in adult patients, geriatric populations, and in those after bariatric surgery. In conclusion, obesity should be considered as a fracture risk in adults, as well as falls and fractures in geriatric patients, in particular in those with sarcopenic obesity, and after bariatric surgery. The specific characteristics of fractures risk associated with obesity should be considered by physicians in the diagnostic and therapeutic work-up of obese patients. This review outlines the current literature on this topic and aims to guide physicians regarding proper decisions to prevent fractures in patients with obesity.

miRNAs and isomiRs: Serum-Based Biomarkers for the Development of Intellectual Disability and Autism Spectrum Disorder in Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterized by a high incidence of epilepsy and neuropsychiatric manifestations known as tuberous-sclerosis-associated neuropsychiatric disorders (TANDs), including autism spectrum disorder (ASD) and intellectual disability (ID). MicroRNAs (miRNAs) are small regulatory non-coding RNAs that regulate the expression of more than 60% of all protein-coding genes in humans and have been reported to be dysregulated in several diseases, including TSC. In the current study, RNA sequencing analysis was performed to define the miRNA and isoform (isomiR) expression patterns in serum. A Receiver Operating Characteristic (ROC) curve analysis was used to identify circulating molecular biomarkers, miRNAs, and isomiRs, able to discriminate the development of neuropsychiatric comorbidity, either ASD, ID, or ASD + ID, in patients with TSC. Part of our bioinformatics predictions was verified with RT-qPCR performed on RNA isolated from patients' serum. Our results support the notion that circulating miRNAs and isomiRs have the potential to aid standard clinical testing in the early risk assessment of ASD and ID development in TSC patients.

Vitamin D Deficiency in Older Patients-Problems of Sarcopenia, Drug Interactions, Management in Deficiency.

Vitamin D deficiency frequently occurs in older people, especially in individuals with comorbidity and polypharmacotherapy. In this group, low vitamin D plasma concentration is related to osteoporosis, osteomalacia, sarcopenia and myalgia. Vitamin D levels in humans is an effect of the joint interaction of all vitamin D metabolic pathways. Therefore, all factors interfering with individual metabolic stages may affect 25-hydroxyvitamin D plasma concentration. The known factors affecting vitamin D metabolism interfere with cytochrome CYP3A4 activity. There is another group of factors that impairs intestinal vitamin D absorption. The phenomenon of drugs and vitamin D interactions is observed first and foremost in patients with comorbidity. This is a typical situation, where the absence of "hard evidence" is not synonymous with the possible lack of adverse effects. Osteoporosis and sarcopenia (generalized and progressive decrease of skeletal muscle mass and strength) are some of the musculoskeletal consequences of hypovitaminosis D. These consequences are related to an increased risk of adverse outcomes, including bone fractures, physical disabilities, and a lower quality of life. This can lead not only to an increased risk of falls and fractures but is also one of the main causes of frailty syndrome in the aging population. Generally, Vitamin D plasma concentration is significantly lower in subjects with osteoporosis and muscle deterioration. In some observational and uncontrolled treatment studies, vitamin D supplementation resulted in a reduction of proximal myopathy and muscle pain. The most conclusive results were found in subjects with severe vitamin D deficiency and in patients avoiding large doses of vitamin D. However, the role of vitamin D in muscle pathologies is not clear and research has provided conflicting results. This is plausibly due to the heterogeneity of the subjects, vitamin D doses and environmental factors. This report presents data on some problems with vitamin D deficiency in the elderly population and the management of vitamin D deficiency D in successful or unsuccessful aging.

Immune Dysregulation in Patients With Chromosome 18q Deletions-Searching for Putative Loci for Autoimmunity and Immunodeficiency.

Introduction: Autoimmune disorders, IgA deficiency, and allergies seem to be common among individuals with 18q deletion syndrome [OMIM 601808]. We aimed to determine the prevalence, mechanism, and genetic background of autoimmunity, immune deficiency, and allergy in a cohort of patients with 18q deletions. Material and Methods: Medical registries and social media were used to recruit the patients. Microarray oligonucleotide comparative genomic hybridization (aCGH) (Agilent, Santa Clara, CA, USA) was performed in all patients to identify size and location of chromosome 18 deletion. Clinical evaluation and medical record collection were performed in each of the study participants. The history of autoimmune disorders, severe and/or recurrent infections, and symptoms of allergy were noted. Total immunoglobulin IgG, IgA, IgM, IgE, and IgG1-4 serum levels were measured using nephelometry and ELISA methods. Lymphocyte T subset phenotyping was performed in 24 subjects from 18q del cohort. To predict the most promising candidate genes, we used the ENDEAVOUR-a free web resource for gene prioritization. Results: 18q deletion was confirmed by means of array CGH analysis in 27 individuals, 15 (55.6%) females and 12 males, referred to the project by specialists in medical genetics, diabetology, or pediatric endocrinology between May 2015 and December 2019. The mean age at examination was 11.8 years (min-max: 4.0-33.5). Autoimmune disorders were present in 14/27 (51.8%) of the cohort. In eight of patients, symptoms of immune deficiency coexisted with autoimmunity. Allergy was reported in nine of 27 (33.4%) patients. Over 89% of patients presented with at list one type of immunoglobulin (IgA, IgM, IgG, IgE, and IgG1-4) deficiency and eight of 25 (32%) had abnormalities in at least two major immunoglobulin (IgG, IgA, IgM) measurements (CVID-like phenotype). Patients with 18q del exhibited a significantly decreased CD4, Treg FOXP3+, TregFOXP3+Helios+, and TemCD4 cell numbers in comparison with the control groups of 24 T1DM patients and 28 healthy controls. Conclusions: Patients with 18q deletions frequently suffer from autoimmune disorders, recurrent infections, and allergy due to immune dysregulation presenting with variable antibody deficiencies and T-regulatory cell deficiency (CD4+CD25+CD127lowFOXP3+). The spectrum of speculations regarding which gene might be responsible for such phenotype ranges from single gene haploinsufficiency to deletion of a cluster of immunogenes located distally to 18q21.

Age-related differences in vitamin D status in Polish centenarians compared with 65-year-olds.

INTRODUCTION: Vitamin D status is known to change with age. However, little is known about vitamin D status in centenarians. OBJECTIVES: The aim of the study was to assess vitamin D status and correlations among the levels of parathyroid hormone (PTH), 25­hydroxycholecalciferol (25[OH]D), 1,25-dihydroxycholecalciferol (1,25[OH]D), calcium, inorganic phosphorus, and alkaline phosphatase (ALP) activity in centenarians. PATIENTS AND METHODS: The study group included 97 participants: 81 women and 16 men (median [interquartile range [IQR]) age, 101.4 [100.5-102.16] years). Centenarians were visited at their homes where examinations were conducted and blood samples collected. The control group consisted of 57 elderly subjects: 35 women and 22 men (median [IQR] age, 65.9 [65.3-66.5] years). The concentrations of PTH, 25(OH)D, and 1,25(OH)D were measured in frozen plasma samples, and calcium, phosphorus, and ALP levels, in serum samples. RESULTS: The median calcium level was 8.88 mg/dl in centenarians versus 9.52 mg/dl in 65­year-old subjects (P <0.01); ALP, 223 IU versus 190 IU (P = 0.01); phosphorus, 3.01 mg/dl versus 3.23 mg/dl (P = 0.13); PTH, 45.59 pg/ml versus 29.27 pg/ml (P <0.01); 25(OH)D, 7.39 ng/ml versus 19.81 ng/ml (P <0.01); 1,25(OH)D, 57.5 pmol/l versus 78.6 pmol/l (P <0.01). Only centenarians demonstrated correlations among the measured laboratory parameters. CONCLUSIONS: Considering lower 25(OH)D, 1,25(OH)D, and calcium concentrations in the majority of centenarians, as well as the negative correlation between vitamin D active metabolites and PTH, vitamin D and calcium should be systematically supplemented in the oldest of the elderly.

Cytosolic translational responses differ under conditions of severe short-term and long-term mitochondrial stress.

Previous studies demonstrated that cells inhibit protein synthesis as a compensatory mechanism for mitochondrial dysfunction. Protein synthesis can be attenuated by 1) the inhibition of mTOR kinase, which results in a decrease in the phosphorylation of S6K1 and 4E-BP1 proteins, and 2) an increase in the phosphorylation of eIF2α protein. The present study investigated both of these pathways under conditions of short-term acute and long-term mitochondrial stress. Short-term responses were triggered in mammalian cells by treatment with menadione, antimycin A, or CCCP. Long-term mitochondrial stress was induced by prolonged treatment with menadione or rotenone and expression of genetic alterations, such as knocking down the MIA40 oxidoreductase or knocking out NDUFA11 protein. Short-term menadione, antimycin A, or CCCP cell treatment led to the inhibition of protein synthesis, accompanied by a decrease in mTOR kinase activity, an increase in the phosphorylation of eIF2α (Ser51), and an increase in the level of ATF4 transcription factor. Conversely, long-term stress led to a decrease in eIF2α (Ser51) phosphorylation and ATF4 expression and to an increase in S6K1 (Thr389) phosphorylation. Thus, under long-term mitochondrial stress, cells trigger long-lasting adaptive responses for protection against excessive inhibition of protein synthesis.

GSK3ß activity alleviates epileptogenesis and limits GluA1 phosphorylation.

BACKGROUND: Glycogen synthase kinase-3ß (GSK3ß) is a key regulator of cellular homeostasis. In neurons, GSK3ß contributes to the control of neuronal transmission and plasticity, but its role in epilepsy remains to be defined. METHODS: Biochemical and electrophysiological methods were used to assess the role of GSK3ß in regulating neuronal transmission and epileptogenesis. GSK3ß activity was increased genetically in GSK3ß[S9A] mice. Its effects on neuronal transmission and epileptogenesis induced by kainic acid were assessed by field potential recordings in mice brain slices and video electroencephalography in vivo. The ion channel expression was measured in brain samples from mice and followed by analysis in samples from patients with temporal lobe epilepsy or focal cortical dysplasia in correlation to GSK3ß phosphorylation. FINDINGS: Higher GSK3ß activity decreased the progression of kainic acid induced epileptogenesis. At the biochemical level, higher GSK3ß activity increased the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel 4 under basal conditions and in the epileptic mouse brain and decreased phosphorylation of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 at Serine 831 under basal conditions. Moreover, we found a significant correlation between higher inhibitory GSK3ß phosphorylation at Serine 9 and higher activating GluA1 phosphorylation at Serine 845 in brain samples from epileptic patients. INTERPRETATION: Our data imply GSK3ß activity in the protection of neuronal networks from hyper-activation in response to epileptogenic stimuli and indicate that the anti-epileptogenic function of GSK3ß involves modulation of HCN4 level and the synaptic AMPA receptors pool.