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UFGI Publications Round-up Week 12/05/2016

Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration.

Author information: Yang F1, Ma H1, Belcher J1, Butler MR1, Redmond TM2, Boye SL3,4, Hauswirth WW3,4, Ding XQ5.

1Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
2Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, Bethesda, Maryland, USA.
3Department of Ophthalmology, University of Florida, Gainesville, Florida, USA; and.
4Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA.
5Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; xi-qin-ding@ouhsc.edu.

Journal: FASEB Journal

Date of e-pub: December 2016

Abstract: Recent studies have implicated thyroid hormone (TH) signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we found that antithyroid treatment preserves cones. This work investigates the significance of targeting intracellular TH components locally in the retina. The cellular TH level is mainly regulated by deiodinase iodothyronine (DIO)-2 and -3. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which binds to the TH receptor, whereas DIO3 degrades T3 and T4. We examined cone survival after overexpression of DIO3 and inhibition of DIO2 and demonstrated the benefits of these manipulations. Subretinal delivery of AAV5-IRBP/GNAT2-DIO3, which directs expression of human DIO3 specifically in cones, increased cone density by 30-40% in a Rpe65-/- mouse model of Lebers congenital amaurosis (LCA) and in a Cpfl1 mouse with Pde6c defect model of achromatopsia, compared with their respective untreated controls. Intravitreal and topical delivery of the DIO2 inhibitor iopanoic acid also significantly improved cone survival in the LCA model mice. Moreover, the expression levels of DIO2 and Slc16a2 were significantly higher in the diseased retinas, suggesting locally elevated TH signaling. We show that targeting DIOs protects cones, and intracellular inhibition of TH components locally in the retina may represent a novel strategy for retinal degeneration management.

 

 

In vivo tissue-tropism of adeno-associated viral vectors.

Author information: Srivastava A1.

1Division of Cellular and Molecular Therapy, Department of Pediatrics, Powell Gene Therapy Center, University of Florida College of Medicine, 2033 Mowry Road, Gainesville, FL 32611, United States; Department of Molecular Genetics & Microbiology, Powell Gene Therapy Center, University of Florida College of Medicine, 2033 Mowry Road, Gainesville, FL 32611, United States. Electronic address: aruns@peds.ufl.edu.

Journal: Current Opinion in Virology

Date of e-pub: December 2016

Abstract: In this review, a brief account of the historical perspective of the discovery of the first cellular receptor and co-receptor of the prototype adeno-associated virus serotype 2 (AAV2) will be presented. The Subsequent discovery of a number of AAV serotypes, and attempts to identify the cellular receptors and co-receptors for these serotype vectors has had significant implications in their use in human gene therapy. As additional AAV serotypes are discovered and isolated, a detailed understanding of their tropism is certainly likely to play a key role in all future studies, both basic science as well as clinical.

 

 

Mutations in PROSC Disrupt Cellular Pyridoxal Phosphate Homeostasis and Cause Vitamin-B6-Dependent Epilepsy.

Author information: Darin N1, Reid E2, Prunetti L3, Samuelsson L4, Husain RA5, Wilson M2, El Yacoubi B3, Footitt E6, Chong WK7, Wilson LC8, Prunty H9, Pope S10, Heales S11, Lascelles K12, Champion M13, Wassmer E14, Veggiotti P15, de Crécy-Lagard V3, Mills PB16, Clayton PT17.

1Department of Pediatrics, University of Gothenburg and Sahlgrenska University Hospital, 41685 Gothenburg, Sweden.
2Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
3Department of Microbiology and Cell Science, Institute for Food and Agricultural Sciences and Genetic Institute, University of Florida, Gainesville, FL 32611, USA.
4Department of Clinical Genetics, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden.
5Centre for Inborn Metabolic Disorders, Department of Neuropediatrics, Jena University Hospital, 07740 Jena, Germany.
6Department of Metabolic Medicine, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK.
7Department of Radiology, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK.
8Department of Clinical Genetics, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK.
9Department of Chemical Pathology, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK.
10Neurometabolic Unit, National Hospital, Queen Square, London WC1N 3BG, UK.
11Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK; Department of Chemical Pathology, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK; Neurometabolic Unit, National Hospital, Queen Square, London WC1N 3BG, UK.
12Department of Neuroscience, Evelina London Children’s Hospital, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK.
13Department of Inherited Metabolic Disease, Evelina London Children’s Hospital, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK.
14Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, UK.
15Department of Child Neurology and Psychiatry, C. Mondino National Neurological Institute, Mondino 2, 27100 Pavia, Italy; Brain and Behaviour Department, University of Pavia, Strada Nuova, 65 Pavia, Italy.
16Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK. Electronic address: p.mills@ucl.ac.uk.
17Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK. Electronic address: peter.clayton@ucl.ac.uk.

Journal: American Journal of Human Genetics

Date of e-pub: December 2016

Abstract: Pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms that are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B6 vitamer metabolism or by inactivation of PLP, which can occur when compounds accumulate as a result of inborn errors of other pathways or when small molecules are ingested. Whole-exome sequencing of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial), PROSC, which encodes a PLP-binding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified four additional children with biallelic PROSC mutations. Pre-treatment cerebrospinal fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent enzymes. However, cultured fibroblasts showed excessive PLP accumulation. An E.coli mutant lacking the PROSC homolog (ΔYggS) is pyridoxine sensitive; complementation with human PROSC restored growth whereas hPROSC encoding p.Leu175Pro, p.Arg241Gln, and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells, which is how to supply enough PLP for apoenzymes while maintaining free PLP concentrations low enough to avoid unwanted reactions with other important cellular nucleophiles. Although the mechanism involved is not fully understood, our studies suggest that PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor to apoenzymes while minimizing any toxic side reactions.

 

 

The mammalian LINC complex regulates genome transcriptional responses to substrate rigidity.

Author information: Alam SG1, Zhang Q1, Prasad N2, Li Y1, Chamala S3, Kuchibhotla R1, Kc B4, Aggarwal V1, Shrestha S2,5, Jones AL2, Levy SE2, Roux KJ4, Nickerson JA6, Lele TP1.

1Department of Chemical Engineering, University of Florida, Bldg. 723, Gainesville, FL 32611, USA.
2HudsonAlpha Institute of Biotechnology, Huntsville, AL, 35806, USA.
3Department of Biology, University of Florida, Cancer and Genetics Research Complex, 2033 Mowry Road, Gainesville, FL 32610, USA.
4Sanford Children’s Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA, Gainesville, FL 32610, USA.
5Department of Biological Sciences, University of Alabama in Huntsville, Huntsville, AL 35186, USA.
6Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

Journal: Science Reports

Date of e-pub: December 2016

Abstract: Mechanical integration of the nucleus with the extracellular matrix (ECM) is established by linkage between the cytoskeleton and the nucleus. This integration is hypothesized to mediate sensing of ECM rigidity, but parsing the function of nucleus-cytoskeleton linkage from other mechanisms has remained a central challenge. Here we took advantage of the fact that the LINC (linker of nucleoskeleton and cytoskeleton) complex is a known molecular linker of the nucleus to the cytoskeleton, and asked how it regulates the sensitivity of genome-wide transcription to substratum rigidity. We show that gene mechanosensitivity is preserved after LINC disruption, but reversed in direction. Combined with myosin inhibition studies, we identify genes that depend on nuclear tension for their regulation. We also show that LINC disruption does not attenuate nuclear shape sensitivity to substrate rigidity. Our results show for the first time that the LINC complex facilitates mechano-regulation of expression across the genome.

NOTE: These abstracts were retrieved from the U.S. National Library of Medicine website managed in collaboration with the U.S. National Library of Medicine

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