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A transgenic minipig model of Huntington's Disease

Baxa, Monika
Author Baxa, Monika Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, v.v.i., AS CR, Libechov, Czech Republic Faculty of Science, Department of Cell Biology, Charles University in Prague, Prague, Czech Republic
Hruska-Plochan, Marian
Author Hruska-Plochan, Marian Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, v.v.i., AS CR, Libechov, Czech Republic Faculty of Science, Department of Cell Biology, Charles University in Prague, Prague, Czech Republic Neurodegeneration Laboratory, Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA Sanford Consortium for Regenerative Medicine, San Diego, La Jolla, CA, USA
Juhas, Stefan
Author Juhas, Stefan Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, v.v.i., AS CR, Libechov, Czech Republic
Vodicka, Petr
Author Vodicka, Petr Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, v.v.i., AS CR, Libechov, Czech Republic Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
Pavlok, Antonin
Author Pavlok, Antonin Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, v.v.i., AS CR, Libechov, Czech Republic
Juhasova, Jana
Author Juhasova, Jana Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, v.v.i., AS CR, Libechov, Czech Republic
Miyanohara, Atsushi
Author Miyanohara, Atsushi Vector Development Laboratory, Human Gene Therapy Program, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
Nejime, Tetsuya
Author Nejime, Tetsuya Neurodegeneration Laboratory, Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA
Klima, Jiri
Author Klima, Jiri Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, v.v.i., AS CR, Libechov, Czech Republic
Macakova, Monika
Author Macakova, Monika Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, v.v.i., AS CR, Libechov, Czech Republic Faculty of Science, Department of Cell Biology, Charles University in Prague, Prague, Czech Republic
Marsala, Silvia
Author Marsala, Silvia Neurodegeneration Laboratory, Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA Sanford Consortium for Regenerative Medicine, San Diego, La Jolla, CA, USA
Weiss, Andreas
Author Weiss, Andreas Novartis Institutes for Biomedical Research, Neuroscience Discovery, Basel, Switzerland IRBM Promidis, Pomezia, Italy
Kubickova, Svatava
Author Kubickova, Svatava Department of Genetics and Reproduction, Veterinary Research Institute, Brno, Czech Republic
Musilova, Petra
Author Musilova, Petra Department of Genetics and Reproduction, Veterinary Research Institute, Brno, Czech Republic
Vrtel, Radek
Author Vrtel, Radek Department of Clinical Genetics and Fetal Medicine, Palacky University, University Hospital Olomouc, Olomouc, Czech Republic
Sontag, Emily M
Author Sontag, Emily M Department of Biological Chemistry University of California, Irvine, CA, USA Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA
Thompson, Leslie M
Author Thompson, Leslie M Department of Biological Chemistry University of California, Irvine, CA, USA Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA Department of Neurobiology and Behavior University of California, Irvine, CA, USA
Schier, Jan
Author Schier, Jan Institute of Information Theory and Automation v.v.i., AS CR, Prague, Czech Republic
Hansikova, Hana
Author Hansikova, Hana Laboratory for Study of Mitochondrial Disorders, First Faculty of Medicine, Department of Pediatrics and Adolescent Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
Howland, David S
Author Howland, David S CHDI Foundation, Princeton, NY, USA
Cattaneo, Elena
Author Cattaneo, Elena Department of Pharmacological Sciences and Centre for Stem Cell Research, Università degli Studi di Milano, Milan, Italy
DiFiglia, Marian
Author DiFiglia, Marian Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
Marsala, Martin
Author Marsala, Martin Neurodegeneration Laboratory, Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA Sanford Consortium for Regenerative Medicine, San Diego, La Jolla, CA, USA Institute of Neurobiology, Slovak Academy of Sciences, Kosice, Slovak Republic
Motlik, Jan
Author Motlik, Jan Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, v.v.i., AS CR, Libechov, Czech Republic

Journal of Huntington's disease. 2013 ; 2 (1) : 47-68.

J Huntingtons Dis
ISSN 1879-6397
Source

Language English Country United States Media print

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/pmid25063429

PubMed 25063429
DOI 10.3233/jhd-130001
PII: 457K261J8164V348
Knihovny.cz E-resources

Keywords
AGERA assay, DARPP32, FISH analysis, Huntington's disease, TR-FRET assay, immunohistochemistry, large animal model, lentiviral transgenesis, mRNA and protein expression, minipigs, mutant huntingtin, spermatozoa,
MeSH
Genetic Vectors MeSH
Animals, Genetically Modified * MeSH
Huntington Disease * MeSH
In Situ Hybridization MeSH
Lentivirus MeSH
Swine, Miniature MeSH
Disease Models, Animal * MeSH
Polymerase Chain Reaction MeSH
Swine MeSH
Huntingtin Protein MeSH
Nerve Tissue Proteins genetics MeSH
Transduction, Genetic MeSH
Transgenes MeSH
Blotting, Western MeSH
Animals MeSH
Check Tag
Male MeSH
Female MeSH
Animals MeSH
Publication type
Journal Article MeSH
Research Support, Non-U.S. Gov't MeSH
Names of Substances
HTT protein, human MeSH Browser
Huntingtin Protein MeSH
Nerve Tissue Proteins MeSH

BACKGROUND: Some promising treatments for Huntington's disease (HD) may require pre-clinical testing in large animals. Minipig is a suitable species because of its large gyrencephalic brain and long lifespan. OBJECTIVE: To generate HD transgenic (TgHD) minipigs encoding huntingtin (HTT)1-548 under the control of human HTT promoter. METHODS: Transgenesis was achieved by lentiviral infection of porcine embryos. PCR assessment of gene transfer, observations of behavior, and postmortem biochemical and immunohistochemical studies were conducted. RESULTS: One copy of the human HTT transgene encoding 124 glutamines integrated into chromosome 1 q24-q25 and successful germ line transmission occurred through successive generations (F0, F1, F2 and F3 generations). No developmental or gross motor deficits were noted up to 40 months of age. Mutant HTT mRNA and protein fragment were detected in brain and peripheral tissues. No aggregate formation in brain up to 16 months was seen by AGERA and filter retardation or by immunostaining. DARPP32 labeling in WT and TgHD minipig neostriatum was patchy. Analysis of 16 month old sibling pairs showed reduced intensity of DARPP32 immunoreactivity in neostriatal TgHD neurons compared to those of WT. Compared to WT, TgHD boars by one year had reduced fertility and fewer spermatozoa per ejaculate. In vitro analysis revealed a significant decline in the number of WT minipig oocytes penetrated by TgHD spermatozoa. CONCLUSIONS: The findings demonstrate successful establishment of a transgenic model of HD in minipig that should be valuable for testing long term safety of HD therapeutics. The emergence of HD-like phenotypes in the TgHD minipigs will require more study.

CHDI Foundation Princeton NY USA

Department of Biological Chemistry University of California Irvine CA USA Department of Psychiatry and Human Behavior University of California Irvine CA USA

Department of Biological Chemistry University of California Irvine CA USA Department of Psychiatry and Human Behavior University of California Irvine CA USA Department of Neurobiology and Behavior University of California Irvine CA USA

Department of Clinical Genetics and Fetal Medicine Palacky University University Hospital Olomouc Olomouc Czech Republic

Department of Genetics and Reproduction Veterinary Research Institute Brno Czech Republic

Department of Neurology Massachusetts General Hospital Boston MA USA

Department of Pharmacological Sciences and Centre for Stem Cell Research Università degli Studi di Milano Milan Italy

Institute of Information Theory and Automation v v i AS CR Prague Czech Republic

Laboratory for Study of Mitochondrial Disorders 1st Faculty of Medicine Department of Pediatrics and Adolescent Medicine Charles University and General University Hospital Prague Prague Czech Republic

Laboratory of Cell Regeneration and Plasticity Institute of Animal Physiology and Genetics v v i AS CR Libechov Czech Republic

Laboratory of Cell Regeneration and Plasticity Institute of Animal Physiology and Genetics v v i AS CR Libechov Czech Republic Department of Neurology Massachusetts General Hospital Boston MA USA

Laboratory of Cell Regeneration and Plasticity Institute of Animal Physiology and Genetics v v i AS CR Libechov Czech Republic Faculty of Science Department of Cell Biology Charles University Prague Prague Czech Republic Neurodegeneration Laboratory Department of Anesthesiology University of California San Diego La Jolla CA USA Sanford Consortium for Regenerative Medicine San Diego La Jolla CA USA