A5054438079- Mitochondrial Function and Pathology
- Glycosylation and Glycoproteins Research
- Inflammatory Myopathies and Dermatomyositis
- Metabolism and Genetic Disorders
- RNA modifications and cancer
- Calcium signaling and nucleotide metabolism
- Adenosine and Purinergic Signaling
- Pancreatic function and diabetes
- Chronic Lymphocytic Leukemia Research
- Erythrocyte Function and Pathophysiology
- Renal Diseases and Glomerulopathies
- Celiac Disease Research and Management
- Coenzyme Q10 studies and effects
- Galectins and Cancer Biology
- MicroRNA in disease regulation
- CAR-T cell therapy research
- Virus-based gene therapy research
- Diet and metabolism studies
- Viral Infectious Diseases and Gene Expression in Insects
- Biochemical and Molecular Research
- Genetics and Neurodevelopmental Disorders
- Neurogenetic and Muscular Disorders Research
- Genetic Neurodegenerative Diseases
- Glycogen Storage Diseases and Myoclonus
- Hepatocellular Carcinoma Treatment and Prognosis
Children's Hospital of Philadelphia
2017-2025
Sheba Medical Center
2022-2025
Edmond and Lily Safra Children's Hospital
2025
National Human Genome Research Institute
2009-2019
National Institutes of Health
2009-2019
Weizmann Institute of Science
2016-2018
Tel Aviv University
2009-2014
Migal - Galilee Technology Center
2008-2010
Changes in the gut microbiota and mitochondrial genome are both linked with development of disease. To investigate why, we examined mice harboring various mutations genes that alter function. These studies revealed genetic variations altered composition community. In cross-fostering studies, found although initial community newborn was obtained from nursing mother, progressed toward characteristic microbiome unfostered pups same genotype within 2 months. Analysis DNA variants associated...
Mitochondrial DNA (mtDNA) is highly polymorphic, and host mtDNA variation has been associated with altered cancer severity. To determine the basis of this mtDNA–cancer association, we analyzed conplastic mice C57BL/6J (B6) nucleus but two naturally occurring lineages, B6 NZB , where mitochondria generate more oxidative phosphorylation (OXPHOS)-derived reactive oxygen species (mROS). In a cardiac transplant model, Foxp3+ T regulatory (Treg) cells supported long-term allograft survival,...
Cellular distribution and dynamics of mitochondria are regulated by several motor proteins a microtubule network. In neurons, mitochondrial trafficking is crucial because high energy needs calcium ion buffering along axons to synapses during neurotransmission. The kinesin (TRAKs) well characterized for their role in lysosomal cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants TRAK1 (NM_001042646:c.287-2A > C), six lethal encephalopathic...
Primary coenzyme Q10 (CoQ
Autism spectrum disorders (ASDs) are characterized by a deficit in social communication, pathologic repetitive behaviors, restricted interests, and electroencephalogram (EEG) aberrations. While exhaustive analysis of nuclear DNA (nDNA) variation has revealed hundreds copy number variants (CNVs) loss-of-function (LOF) mutations, no unifying hypothesis as to the pathophysiology ASD yet emerged. Based on biochemical physiological analyses, it been hypothesized that may be result systemic...
Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult-onset due to mutations in the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) gene. Affected patients have no therapeutic options. We previously demonstrated preclinical testing ability safely correct gene function through liposomal delivery of wild-type Results were verified a single patient treated by intravenous infusion lipoplex. A (patient 001) with severe HIBM compassionate investigational...
Mitochondrial dysfunction can be associated with a range of clinical manifestations. Here, we report family complex phenotype including combinations connective tissue, neurological, and metabolic symptoms that were passed on to all surviving children. Analysis the maternally inherited mtDNA revealed novel genotype encompassing haplogroup J - defining mitochondrial DNA (mtDNA) ND5 m.13708G>A (A458T) variant arising H7A background, an extremely rare combination. transmitochondrial cybrids...
Pathological glomerular hyposialylation has been implicated in certain unexplained glomerulopathies, including minimal change nephrosis, membranous glomerulonephritis, and IgA nephropathy. We studied our previously established mouse model carrying a homozygous mutation the key enzyme of sialic acid biosynthesis, N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. Mutant mice died before postnatal day 3 (P3) from severe glomerulopathy with podocyte effacement segmental basement...
UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) catalyzes the first two committed steps in sialic acid synthesis. In addition to three previously described human GNE isoforms (hGNE1-hGNE3), our database and polymerase chain reaction analysis yielded five additional (hGNE4-hGNE8). hGNE1 is ubiquitously expressed major isoform, while hGNE2-hGNE8 are differentially may act as tissue-specific regulators of sialylation. hGNE2 hGNE7 display a 31-residue N-terminal extension compared hGNE1. On basis...
Abstract microRNAs (miRNAs) are critical for neuronal function and their dysregulation is repeatedly observed in neurodegenerative diseases. Here, we implemented high content image analysis investigating the impact of several miRNAs mouse primary motor neurons. This survey directed our attention to neuron-specific miR-124, which controls axonal morphology. By performing next generation sequencing molecular studies, characterized novel roles miR-124 control mitochondria localization function....
The exact pathomechanism of GNE myopathy remains elusive, but likely involves aberrant sialylation. We explored sialylation status blood-based glycans as potential disease markers.We employed immunoblotting, lectin histochemistry and mass spectrometry.GNE muscle showed hyposialylation predominantly O-linked glycans. glycome patients' plasma compared with controls increased amounts desialylated Thomsen-Friedenreich (T)-antigen, and/or decreased its sialylated form, ST-antigen. Importantly,...
Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of both humans mice cause cardiomyopathy myopathy associated with exercise intolerance weakness. Here we decipher molecular underpinnings ANT1-deficiency-mediated intolerance. This was achieved correlating physiology, mitochondrial function metabolomics deficient ANT1 comparing this to control mice. We demonstrate a peripheral...
Summary Hyperphenylalaninemia (HPA) is a group of diseases characterized by persistent elevation phenylalanine levels in tissues and biological fluids. The most frequent form hydroxylase deficiency, causing phenylketonuria (PKU). Among 159 Israeli patients (Jews, Muslim Christian Arabs Druze) with HPA, whom at least one the mutations was characterized, total 43 different were detected, including seven novel ones. PKU very rare among Ashkenazi Jews relatively from Yemen, Caucasian Mountains,...
The bifunctional enzyme UDP-GlcNAc 2-epimerase/ ManNAc kinase (GNE/MNK), encoded by the GNE gene, catalyzes first two committed, rate-limiting steps in biosynthesis of N-acetylneuraminic acid (sialic acid). GNE/MNK is feedback inhibited binding downstream product, CMP-sialic its allosteric site. mutations can result human disorders, hereditary inclusion body myopathy (HIBM) or sialuria. So far, no active site geometry predictions conformational transitions involved with function are...
IntroductionSialic acids are important contributors to the polyanionic component of glomerular filtration barrier, which regulates permeability selectivity. Pathologic hyposialylation, associated with podocyte effacement, has been implicated in human and mouse glomerulopathies. Oral treatment N-acetylmannosamine (ManNAc), uncharged precursor sialic acid, ameliorates pathology different models disease.MethodsHere we explore sialylation status kidney biopsies obtained from 27 subjects various...