Felsenstein Medical Research Center
Felsenstein Medical Research Center
Gothelf D.,Edmond and Lily Safra Childrens Hospital |
Gothelf D.,Tel Aviv University |
Law A.J.,Aurora University |
Law A.J.,U.S. National Institutes of Health |
And 14 more authors.
Biological Psychiatry | Year: 2014
Background 22q11.2 deletion syndrome (22q11.2DS) is the most common genetic syndrome associated with schizophrenia. The catechol-O-methyltransferase (COMT) gene is located in the obligatory deletion region, and possible associations between COMT variants and neuropsychiatric manifestations in 22q11.2DS have been reported. The purpose of the current study was to evaluate the effect of COMT hemizygosity and molecular haplotypes on gene expression and enzyme activity and its association with psychotic symptoms in 22q11.2DS. Methods Lymphoblast samples were drawn from 53 individuals with 22q11.2DS and 16 typically developing control subjects. We measured COMT messenger (m)RNA and protein expression and enzyme activity using standard procedures. The presence of a psychotic disorder and cognitive deficits were also evaluated using structured testing. Results There was an approximately 50% reduction in COMT mRNA, protein, and enzyme activity levels in 22q11.2DS samples. Haplotype analysis revealed clear phenotypic differences between various Val-containing haplotypes on COMT-3′ untranslated region extended mRNA, soluble COMT and membrane-bound proteins, and enzyme activity. The G variant of rs165599, a 3′ untranslated region single nucleotide polymorphism, was associated with low levels of COMT expression and with the presence of psychosis and lower performance IQ scores in our 22q11.2DS sample. Finally, we demonstrate that the COMT rs74745580 "T" mutation is associated with absent soluble COMT expression and very low COMT activity in two 22q11.2DS individuals. Conclusions Our findings confirm a robust effect of COMT hemizygosity on COMT activity and show complex interactions of variants within the COMT gene that influence COMT biology and confound conclusions based on associations with the Val158Met genotype alone. © 2014 Society of Biological Psychiatry.
Benkler C.,Tel Aviv University |
Barhum Y.,Tel Aviv University |
Ben-Zur T.,Tel Aviv University |
Offen D.,Tel Aviv University |
Offen D.,Felsenstein Medical Research Center
Journal of Molecular Neuroscience | Year: 2016
The 150-year-long search for treatments of amyotrophic lateral sclerosis (ALS) is still fueled by frustration over the shortcomings of available therapeutics. Contributing to the therapeutic limitations might be the targeting of a single aspect of this multifactorial-multisystemic disease. In an attempt to overcome this, we devised a novel multifactorial-cocktail treatment, using lentiviruses encoding: EAAT2, GDH2, and NRF2, that act synergistically to address the band and width of the effected excito-oxidative axis, reducing extracellular-glutamate and glutamate availability while improving the metabolic state and the anti-oxidant response. This strategy yielded particularly impressive results, as all three genes together but not separately prolonged survival in ALS mice by an average of 19–22 days. This was accompanied by improvement in every parameter evaluated, including body-weight loss, reflex score, neurologic score, and motor performance. We hope to provide a novel strategy to slow down disease progression and alleviate symptoms of patients suffering from ALS. © 2015, Springer Science+Business Media New York.
Dadon-Nachum M.,Felsenstein Medical Research Center |
Dadon-Nachum M.,Tel Aviv University |
Melamed E.,Felsenstein Medical Research Center |
Melamed E.,Tel Aviv University |
And 2 more authors.
Journal of Molecular Neuroscience | Year: 2011
Amyotrophic lateral sclerosis (ALS) is a lethal disease, characterized by progressive death of motor neurons with unknown etiology. Evidence from animal models indicates that neuronal dysfunction precedes the clinical phase of the disease. However, in parallel extensive nerve sprouting and synaptic remodeling as part of a compensatory reinnervation processes and possibly also of motor neurons pathology was demonstrated. Therefore, the weakness in muscle groups will not be clinically apparent until a large proportion of motor units are lost. This motor unit loss and associated muscle function which precedes the death of motor neurons may resemble the "die-back" phenomena. Studies indicated that in the early stages the nerve terminals and motor neuron junctions are partially degraded while the cell bodies in the spinal cord are mostly intact. Treatments to rescue motor neurons according to "dying-forward" model of motor neuron pathology in ALS have shown only limited success in SOD1 G93A transgenic mice as well as in humans. If cell body degeneration is late compared with axonal degeneration, early intervention could potentially prevent loss of motor neurons. Therefore, it should be considered, according to the dying back hypothesis, to focus on motor neurons terminals in order to delay or prevent the progressive degradation. © Springer Science+Business Media, LLC 2010.
Shohat M.,Beilinson Hospital |
Shohat M.,Felsenstein Medical Research Center |
Shohat M.,Tel Aviv University |
Halpern G.J.,Beilinson Hospital |
Halpern G.J.,Felsenstein Medical Research Center
Genetics in Medicine | Year: 2011
Familial Mediterranean fever is inherited in an autosomal recessive manner. There are two phenotypes: types 1 and 2. Familial Mediterranean fever type 1 is characterized by recurrent short episodes of inflammation and serositis, including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication. Familial Mediterranean fever type 2 is characterized by amyloidosis as the first clinical manifestation of familial Mediterranean fever in an otherwise asymptomatic individual. Routine treatment of end-stage renal disease, including renal transplantation, is advised. Lifelong treatment with colchicine is required for homozygotes for the p.Met694Val mutation or compound heterozygotes for p.Met694Val and another disease-causing allele; this prevents the inflammatory attacks and the deposition of amyloid. Individuals who do not have the p.Met694Val mutation and who are only mildly affected should be either treated with colchicine or monitored every 6 months for the presence of proteinuria. Molecular genetic testing of the MEFV gene, the only gene currently known to be associated with familial Mediterranean fever, can be offered to family members, especially when the p.Met694Val allele is present, because renal amyloidosis can be prevented by colchicine. © 2011 Lippincott Williams & Wilkins.
Kan I.,Tel Aviv University |
Kan I.,Felsenstein Medical Research Center |
Barhum Y.,Tel Aviv University |
Melamed E.,Tel Aviv University |
Offen D.,Tel Aviv University
Stem Cell Reviews and Reports | Year: 2011
Mammalian neurogenesis has been demonstrated in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. However, the low rate and the restricted long term survival of newborn cells limit the restorative ability of this process. Adult bone marrow derived mesenchymal stem cells (MSCs) have been extensively studied due to their wide therapeutic potential. The aim of this study was to determine if MSC transplantation to the normally restrictive SVZ of mice housed in an enriched environment stimulates endogenous neurogenesis. In the presented study 30 C57BL/6 female mice were divided into 3 groups: standard environment injected with phosphate buffered saline (PBS) and enriched environment injected with either PBS or MSCs. Bromodeoxyuridine was injected for 6 days, and 3 weeks later the mice were sacrificed and the brain tissue analyzed immunohistochemically. PBS-treated mice housed in enriched cages showed augmented neurogenesis in the SGZ but not the SVZ. MSC transplantation was associated with increased proliferation and neuronal differentiation of neural progenitors within the SVZ and an increase in the proportion of the newborn neurons out of the total proliferating cells. Histological analysis confirmed the survival of a significant amount of the transplanted cells at least 3 weeks after transplantation, and the presence of brain-derived neurotrophic factor expression. To our knowledge, this is the first study to show that MSCs might interfere with the tight regulation of the SVZ, independent of the induced brain lesion. © 2011 Springer Science+Business Media, LLC.
Aksanov O.,Ben - Gurion University of the Negev |
Green P.,Felsenstein Medical Research Center |
Green P.,Tel Aviv University |
Birk R.Z.,Ariel University
Cellular and Molecular Life Sciences | Year: 2014
BBS4 is one of several proteins whose defects cause Bardet-Biedl syndrome (BBS), a multi-systemic disorder, manifesting with marked obesity. BBS4 polymorphisms have been associated with common non-syndromic morbid obesity. BBS4 obesity molecular mechanisms, and the role of the BBS4 gene in adipocyte differentiation and function are not entirely known. We now show that Bbs4 plays a direct and essential role in proliferation and adipogenesis: silencing of Bbs4 in 3T3F442A preadipocytes induced accelerated cell division and aberrant differentiation, evident through morphologic studies (light, scanning and transmission electron microscopy), metabolic analyses (fat accumulation, fatty acid profile and lipolysis) and adipogenic markers transcripts (Cebpα, Pparγ, aP2, ADRP, Perilipin). Throughout adipogenesis and when challenged with fat load, Bbs4 silenced cells accumulate significantly more triglycerides than control adipocytes, albeit in smaller (yet greater in number) droplets containing modified fatty acid profiles. Thus, greater fat accumulation in the silenced cells is a consequence of both a higher rate of adipocyte proliferation and of aberrant differentiation leading to augmented aberrant accumulation of fat per cell. Our findings suggest that the BBS obesity might be partly due to a direct role of BBS4 in physiological and pathophysiological mechanisms that underlie adipose tissue formation relevant to obesity. © 2014 Springer.
Simchon-Tenenbaum Y.,Tel Aviv University |
Weizman A.,Research Unit |
Weizman A.,Felsenstein Medical Research Center |
Rehavi M.,Tel Aviv University |
Rehavi M.,Center for the Biology of Addictive Diseases
Behavioural Brain Research | Year: 2015
Attention deficit hyperactivity disorder (ADHD) overdiagnosis and a pharmacological attempt to increase cognitive performance, are the major causes for the frequent (ab)use of psychostimulants in non-ADHD individuals. Methylphenidate is a non-addictive psychostimulant, although its mode of action resembles that of cocaine, a well-known addictive and abused drug. Neuronal- and glial-derived growth factors play a major role in the development, maintenance and survival of neurons in the central nervous system. We hypothesized that methylphenidate and cocaine treatment affect the expression of such growth factors. Beginning on postnatal day (PND) 14, male Sprague Dawley rats were treated chronically with either cocaine or methylphenidate. The rats were examined behaviorally and biochemically at several time points (PND 35, 56, 70 and 90). On PND 56, rats treated with cocaine or methylphenidate from PND 14 through PND 35 exhibited increased hippocampal glial-cell derived neurotrophic factor (GDNF) mRNA levels, after 21 withdrawal days, compared to the saline-treated rats. We found a significant association between cocaine and methylphenidate treatments and age progression in the prefrontal protein expression of brain derived neurotrophic factor (BDNF). Neither treatments affected the behavioral parameters, although acute cocaine administration was associated with increased locomotor activity. It is possible that the increased hippocampal GDNF mRNA levels, may be relevant to the reduced rate of drug seeking behavior in ADHD adolescence that were maintained from childhood on methylphenidate. BDNF protein level increase with age, as well as following stimulant treatments at early age may be relevant to the neurobiology and pharmacotherapy of ADHD. © 2015 Elsevier B.V.
Ankri R.,Bar - Ilan University |
Leshem-Lev D.,Felsenstein Medical Research Center |
Fixler D.,Bar - Ilan University |
Popovtzer R.,Bar - Ilan University |
And 4 more authors.
Nano Letters | Year: 2014
In this study we report the use of gold nanorods (GNRs) as absorption contrast agents in the diffusion reflection (DR) method for the in vivo detection of atherosclerotic injury. The early detection and characterization of atherosclerotic vascular disease is considered to be one of the greatest medical challenges today. We show that macrophage cells, which are major components of unstable active atherosclerotic plaques, uptake gold nanoparticles, resulting in a change in the optical properties of tissue-like phantoms and a unique DR profile. In vivo DR measurements of rats that underwent injury of the carotid artery showed a clear difference between the DR profiles of the injured compared with healthy arteries. The results suggest that DR measurements following GNRs administration represent a potential novel method for the early detection of atherosclerotic vascular disease. © 2014 American Chemical Society.
Maksin-Matveev A.,Bar - Ilan University |
Kanfi Y.,Bar - Ilan University |
Hochhauser E.,Felsenstein Medical Research Center |
Isak A.,Bar - Ilan University |
And 2 more authors.
Experimental Cell Research | Year: 2015
Sirtuin 6 (SIRT6) is a protein associated with prolonged life expectancy. We investigated whether life extension is associated with cardioprotection against hypoxia. The proposed study is to develop approaches to reduce hypoxic damage through the use of the sirtuin pathway and to elucidate the mechanism involved. For that purpose we subjected cardiomyocytes from transgenic mice (TG) with over-expression of SIRT6, to hypoxic stress in cell cultures. We hypothesized that cardiomyocytes from transgenic mice subjected to prolonged hypoxia may release survival factors or fewer damage markers to protect them from hypoxic stress compared with wild type (WT) mice. Lactate dehydrogenase (LDH) and creatine kinase (CK) released to the medium and propidium iodide (PI) binding, were markedly decreased following hypoxia in TG cardiomyocytes. The protective mechanism of SIRT6 over-expression includes the activation of pAMPKα pathway, the increased protein level of B-cell lymphoma 2 (Bcl2), the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), the decrease of reactive oxygen species (ROS) and the reduction in the protein level of phospho-protein kinase B (pAkt) during hypoxia. Together, all these processes impede the necrosis/apoptosis pathways leading to the improved survival of cardiomyocytes following hypoxia, which might explain life extension. © 2014 Elsevier Inc.
Gat-Yablonski G.,Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes |
Gat-Yablonski G.,Felsenstein Medical Research Center
Pediatric Endocrinology Reviews | Year: 2011
The OTX2 gene encodes a key transcription factor in developmental processes. In particular, it is required for the early specification of the brain and the embryonic development of sensory organs, including the pituitary gland, pineal gland, inner part of the ear, eyes, and optic nerve. In later stages, it is important for maintaining intact retina and brain function. Over-expression of OTX2 was found in medulloblastoma, a malignant brain tumor that occurs mainly in childhood. OTX2 mutations are associated with severe ocular phenotypes and central nervous system abnormalities such as seizures, short stature and developmental delay, combined pituitary hormone deficiency (CPHD), structural abnormalities of the pituitary gland and early onset retinal dystrophy. There is no genotype-phenotype correlation and the severity of the disease varies not only by the specific OTX2 mutations but also among individuals harboring the same mutation, suggesting the involvement of multiple levels of regulation.