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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The level of microRNA 21 is upregulated by rapamycin in serum of tuberous sclerosis complex patients and subependymal giant cell astrocytoma (SEGA)-derived cell cultures.

Tuberous sclerosis complex (TSC) represents a genetic condition, in which the clinical manifestations are caused by the disinhibition of the mammalian target of rapamycin (mTOR) pathway due to mutations in the TSC1 (hamartin) or TSC2 (tuberin) genes. The deregulated mTOR activity leads to multi-site tumors, including subependymal giant cell astrocytoma (SEGA). SEGA is a brain tumor that affects around 15% of TSC patients. The aim of the study was to evaluate miR-21 expression in the serum of two groups of TSC patients: with or without SEGA tumors. We found no differences in the level of miR-21 depending on the presence of SEGA. Next, we studied the influence of prolonged rapamycin administration on miR-21 level in the blood serum of TSC patients (6-12 months of rapamycin) and in primary cultures of SEGA-derived cells treated with rapamycin in vitro. Here we show that rapamycin treatment leads to the upregulation of miR-21 in both patients' serum and in primary SEGA tumor cells in the culture indicating the regulatory relationship between rapamycin treatment and miR-21 expression.

Vitamin D Toxicity-A Clinical Perspective.

Confusion, apathy, recurrent vomiting, abdominal pain, polyuria, polydipsia, and dehydration are the most often noted clinical symptoms of vitamin D toxicity (VDT; also called vitamin D intoxication or hypervitaminosis D). VDT and its clinical manifestation, severe hypercalcemia, are related to excessive long-term intake of vitamin D, malfunctions of the vitamin D metabolic pathway, or the existence of coincident disease that produces the active vitamin D metabolite locally. Although VDT is rare, the health effects can be serious if it is not promptly identified. Many forms of exogenous (iatrogenic) and endogenous VDT exist. Exogenous VDT is usually caused by the inadvertent or improper intake of extremely high doses of pharmacological preparations of vitamin D and is associated with hypercalcemia. Serum 25-hydroxyvitamin D [25(OH)D] concentrations higher than 150 ng/ml (375 nmol/l) are the hallmark of VDT due to vitamin D overdosing. Endogenous VDT may develop from excessive production of an active vitamin D metabolite - 1,25(OH)2D in granulomatous disorders and in some lymphomas or from the reduced degradation of that metabolite in idiopathic infantile hypercalcemia. Endogenous VDT may also develop from an excessive production of 25(OH)D and 1,25(OH)2D in congenital disorders, such as Williams-Beuren syndrome. Laboratory testing during routine clinical examinations may reveal asymptomatic hypercalcemia caused by the intake of vitamin D even in doses recommended for the general population and considered safe. That phenomenon, called hypersensitivity to vitamin D, reflects dysregulated vitamin D metabolism. Researchers have proposed many processes to explain VDT. Those processes include elevated activity of 1α-hydroxylase or inhibited activity of 24-hydroxylase, both leading to increased concentration of 1,25(OH)D; increased number of vitamin D receptors; and saturation of the capacity of vitamin D binding protein. Increased public awareness of vitamin D-related health benefits might increase the risk of VDT due to self-administration of vitamin D in doses higher then recommended for age and body weight or even higher than the established upper limit intake values. Consequently, the incidence of hypercalcemia due to hypervitaminosis D might increase.

Liver Angiomyolipomas in Tuberous Sclerosis Complex-Their Incidence and Course.

BACKGROUND: The purpose of this study was to evaluate the epidemiology and clinical significance of hepatic angiomyolipomas in patients with tuberous sclerosis complex. METHODS: We performed a retrospective analysis of clinical and imaging data from 187 patients with tuberous sclerosis complex. The prevalence, progression, and potential relationship between liver lesions and other clinical findings, including genetic associations, were assessed. RESULTS: Twenty-eight of 187 patients (14.9%) had hepatic lesions. There was a predominance of female over male patients in individuals with liver lesions (17 versus 11), with statistical significance in patients under five years of age (P < 0.05). All individuals having hepatic lesions who also had available genetic testing data (n = 20) were diagnosed with a TSC2 gene mutation. All patients with liver lesions had coexisting renal angiomyolipomas (AMLs) (P < 0.05). The age of onset of renal lesions was lower and their prevalence was significantly higher in patients with liver involvement (P < 0.05). In most instances, hepatic lesions measured several millimeters in diameter and were clinically asymptomatic. Progressive lesion growth was documented in six individuals but with no clinical consequences to date. CONCLUSIONS: This study confirms the association of hepatic lesions with TSC2 mutations, a common origin of liver and renal AMLs, as well as the predominance of female patients in this group. Hepatic AMLs are relatively common but mostly benign lesions.

GSK3ß Controls mTOR and Prosurvival Signaling in Neurons.

Glycogen synthase kinases-3ß (GSK3ß) is a key regulator of cell homeostasis. In neurons, GSK3ß contributes to control of neuronal transmission and plasticity. Despite extensive studies in non-neuronal cells, crosstalk between GSK3ß and other signaling pathways remains not well defined in neurons. In the present study, we report that GSK3ß positively affected the activity of effectors of mammalian target of rapamycin complex 1 (mTORC1) and complex 2 (mTORC2), in mature neurons in vitro and in vivo. GSK3ß also promoted prosurvival signaling and attenuated kainic acid-induced apoptosis. Our study identified GSK3ß as a positive regulator of prosurvival signaling, including the mTOR pathway, and indicates the possible neuroprotective role of GSK3ß in models of pharmacologically induced excitotoxicity.

GSK3α and GSK3ß Phosphorylate Arc and Regulate its Degradation.

The selective and neuronal activity-dependent degradation of synaptic proteins appears to be crucial for long-term synaptic plasticity. One such protein is activity-regulated cytoskeleton-associated protein (Arc), which regulates the synaptic content of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), excitatory synapse strength and dendritic spine morphology. The levels of Arc protein are tightly regulated, and its removal occurs via proteasome-mediated degradation that requires prior ubiquitination. Glycogen synthase kinases α and ß (GSK3α, GSKß; collectively named GSK3α/ß) are serine-threonine kinases with abundant expression in the central nervous system. Both GSK3 isozymes are tonically active under basal conditions, but their activity is regulated by intra- and extracellular factors, intimately involved in neuronal activity. Similar to Arc, GSK3α and GSK3ß contribute to synaptic plasticity and the structural plasticity of dendritic spines. The present study identified Arc as a GSK3α/ß substrate and showed that GSKß promotes Arc degradation under conditions that induce de novo Arc synthesis. We also found that GSK3α/ß inhibition potentiated spine head thinning that was caused by the prolonged stimulation of N-methyl-D-aspartate receptors (NMDAR). Furthermore, overexpression of Arc mutants that were resistant to GSK3ß-mediated phosphorylation or ubiquitination resulted in a stronger reduction of dendritic spine width than wildtype Arc overexpression. Thus, GSK3ß terminates Arc expression and limits its effect on dendritic spine morphology. Taken together, the results identify GSK3α/ß-catalyzed Arc phosphorylation and degradation as a novel mechanism for controlling the duration of Arc expression and function.