A Transgenic Minipig Model of Huntington's Disease

Authors

Monika Baxa, Institute of Animal Physiology and Genetics
Marian Hruska-Plochan, Institute of Animal Physiology and Genetics
Stefan Juhas, Institute of Animal Physiology and Genetics
Petr Vodicka, Institute of Animal Physiology and Genetics
Antonin Pavlok, Institute of Animal Physiology and Genetics
Jana Juhasova, Catholic University in Ruzomberok
Atsushi Miyanohara, University of California - San Diego
Tetsuya Nejime, University of California - San Diego
Jiri Klima, Charles University, Prague
Monika Macakova, University of Natural Resources and Life Sciences, Austria
Silvia Marsala, University of California - San Diego
Andreas Weiss, University of Hamburg
Svatava Kubickova, Veterinary Research Institute, Czech Republic
Petra Musilova, Veterinary Research Institute, Czech Republic
Radek Vrtel, Palacky University
Emily M. Sontag, Marquette UniversityFollow
Leslie Thompson, University of California, Irvine
Jan Schier, Institute of Informational Theory and Automation
Hana Hansikova, Charles University, Prague
David S. Howland, CHDI Foundation
Elena Cattaneo, University of Milan
Marian DiFiglia, Massachusetts General Hospital
Martin Marsala, University of California - San Diego
Jan Motlik, Czech Academy of Sciences

Document Type

Article

Publication Date

1-2013

Publisher

IOS Press

Source Publication

Journal of Huntington's Disease

Source ISSN

1879-6397

Original Item ID

DOI: 10.3233/jhd-130001

Abstract

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.

Comments

Published version. Journal of Huntington's Disease, Vol. 2, No. 1 (January 1, 2013): 47-68. DOI. © 2013 IOS Press. Used with permission.

Recommended Citation

Baxa, Monika; Hruska-Plochan, Marian; Juhas, Stefan; Vodicka, Petr; Pavlok, Antonin; Juhasova, Jana; Miyanohara, Atsushi; Nejime, Tetsuya; Klima, Jiri; Macakova, Monika; Marsala, Silvia; Weiss, Andreas; Kubickova, Svatava; Musilova, Petra; Vrtel, Radek; Sontag, Emily M.; Thompson, Leslie; Schier, Jan; Hansikova, Hana; Howland, David S.; Cattaneo, Elena; DiFiglia, Marian; Marsala, Martin; and Motlik, Jan, "A Transgenic Minipig Model of Huntington's Disease" (2013). Biological Sciences Faculty Research and Publications. 904.
https://epublications.marquette.edu/bio_fac/904