Transgenic minipig model of Huntington's disease exhibiting
gradually progressing neurodegeneration

J 2020

Transgenic minipig model of Huntington's disease exhibiting gradually progressing neurodegeneration

ARDAN, Taras, Monika BAXA, Božena LEVINSKÁ, Miroslava SEDLÁČKOVÁ, The Duong NGUYEN et. al.

Basic information

Original name

Transgenic minipig model of Huntington's disease exhibiting gradually progressing neurodegeneration

Authors

ARDAN, Taras (203 Czech Republic), Monika BAXA (203 Czech Republic), Božena LEVINSKÁ (203 Czech Republic), Miroslava SEDLÁČKOVÁ (203 Czech Republic, belonging to the institution), The Duong NGUYEN (203 Czech Republic), Jiří KLÍMA (203 Czech Republic), Štefan JUHÁS (203 Czech Republic), Jana JUHÁSOVÁ (203 Czech Republic), Petra ŠMATLÍKOVÁ (203 Czech Republic), Petra VOCHOZKOVÁ (203 Czech Republic), Jan MOTLÍK (203 Czech Republic) and Zdenka ELLEDEROVÁ (203 Czech Republic, guarantor)

Edition

Disease models & mechanisms, Cambridge, Company of Biologists Ltd. 2020, 1754-8403

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10601 Cell biology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.758

RIV identification code

RIV/00216224:14110/20:00115361

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1242/dmm.041319

UT WoS

000518475500008

Keywords in English

Large animal model; TgHD; Brain; Huntingtin; Neuropathology

Abstract

V originále

Recently developed therapeutic approaches for the treatment of Huntington’s disease (HD) require preclinical testing in large animal models. The minipig is a suitable experimental animal because of its large gyrencephalic brain, body weight of 70-100 kg, long lifespan, and anatomical, physiological and metabolic resemblance to humans. The Libechov transgenic minipig model for HD (TgHD) has proven useful for proof of concept of developing new therapies. However, to evaluate the efficacy of different therapies on disease progression, a broader phenotypic characterization of the TgHD minipig is needed. In this study, we analyzed the brain tissues of TgHD minipigs at the age of 48 and 60-70 months, and compared them to wild-type animals. We were able to demonstrate not only an accumulation of different forms of mutant huntingtin (mHTT) in TgHD brain, but also pathological changes associated with cellular damage caused by mHTT. At 48 months, we detected pathological changes that included the demyelination of brain white matter, loss of function of striatal neurons in the putamen and activation of microglia. At 60-70 months, we found a clear marker of neurodegeneration: significant cell loss detected in the caudate nucleus, putamen and cortex. This was accompanied by clusters of structures accumulating in the neurites of some neurons, a sign of their degeneration that is also seen in Alzheimer’s disease, and a significant activation of astrocytes. In summary, our data demonstrate age-dependent neuropathology with later onset of neurodegeneration in TgHD minipigs.

Citovat

ARDAN, Taras, Monika BAXA, Božena LEVINSKÁ, Miroslava SEDLÁČKOVÁ, The Duong NGUYEN, Jiří KLÍMA, Štefan JUHÁS, Jana JUHÁSOVÁ, Petra ŠMATLÍKOVÁ, Petra VOCHOZKOVÁ, Jan MOTLÍK and Zdenka ELLEDEROVÁ. Transgenic minipig model of Huntington's disease exhibiting gradually progressing neurodegeneration. Disease models & mechanisms. Cambridge: Company of Biologists Ltd., 2020, vol. 13, No 2, p. 1-12. ISSN 1754-8403. Available from: https://dx.doi.org/10.1242/dmm.041319.

@article{1628516,
   author = {Ardan, Taras and Baxa, Monika and Levinská, Božena and Sedláčková, Miroslava and Nguyen, The Duong and Klíma, Jiří and Juhás, Štefan and Juhásová, Jana and Šmatlíková, Petra and Vochozková, Petra and Motlík, Jan and Ellederová, Zdenka},
   article_location = {Cambridge},
   article_number = {2},
   doi = {http://dx.doi.org/10.1242/dmm.041319},
   keywords = {Large animal model; TgHD; Brain; Huntingtin; Neuropathology},
   language = {eng},
   issn = {1754-8403},
   journal = {Disease models & mechanisms},
   title = {Transgenic minipig model of Huntington's disease exhibiting gradually progressing neurodegeneration},
   url = {https://dmm.biologists.org/content/13/2/dmm041319.long},
   volume = {13},
   year = {2020}
}

TY  - JOUR
ID  - 1628516
AU  - Ardan, Taras - Baxa, Monika - Levinská, Božena - Sedláčková, Miroslava - Nguyen, The Duong - Klíma, Jiří - Juhás, Štefan - Juhásová, Jana - Šmatlíková, Petra - Vochozková, Petra - Motlík, Jan - Ellederová, Zdenka
PY  - 2020
TI  - Transgenic minipig model of Huntington's disease exhibiting gradually progressing neurodegeneration
JF  - Disease models & mechanisms
VL  - 13
IS  - 2
SP  - 1-12
EP  - 1-12
PB  - Company of Biologists Ltd.
SN  - 17548403
KW  - Large animal model
KW  - TgHD
KW  - Brain
KW  - Huntingtin
KW  - Neuropathology
UR  - https://dmm.biologists.org/content/13/2/dmm041319.long
L2  - https://dmm.biologists.org/content/13/2/dmm041319.long
N2  - Recently developed therapeutic approaches for the treatment of Huntington’s disease (HD) require preclinical testing in large animal models. The minipig is a suitable experimental animal because of its large gyrencephalic brain, body weight of 70-100 kg, long lifespan, and anatomical, physiological and metabolic resemblance to humans. The Libechov transgenic minipig model for HD (TgHD) has proven useful for proof of concept of developing new therapies. However, to evaluate the efficacy of different therapies on disease progression, a broader phenotypic characterization of the TgHD minipig is needed. In this study, we analyzed the brain tissues of TgHD minipigs at the age of 48 and 60-70 months, and compared them to wild-type animals. We were able to demonstrate not only an accumulation of different forms of mutant huntingtin (mHTT) in TgHD brain, but also pathological changes associated with cellular damage caused by mHTT. At 48 months, we detected pathological changes that included the demyelination of brain white matter, loss of function of striatal neurons in the putamen and activation of microglia. At 60-70 months, we found a clear marker of neurodegeneration: significant cell loss detected in the caudate nucleus, putamen and cortex. This was accompanied by clusters of structures accumulating in the neurites of some neurons, a sign of their degeneration that is also seen in Alzheimer’s disease, and a significant activation of astrocytes. In summary, our data demonstrate age-dependent neuropathology with later onset of neurodegeneration in TgHD minipigs.
ER  -

ARDAN, Taras, Monika BAXA, Božena LEVINSKÁ, Miroslava SEDLÁČKOVÁ, The Duong NGUYEN, Jiří KLÍMA, Štefan JUHÁS, Jana JUHÁSOVÁ, Petra ŠMATLÍKOVÁ, Petra VOCHOZKOVÁ, Jan MOTLÍK and Zdenka ELLEDEROVÁ. Transgenic minipig model of Huntington's disease exhibiting gradually progressing neurodegeneration. \textit{Disease models \&{} mechanisms}. Cambridge: Company of Biologists Ltd., 2020, vol.~13, No~2, p.~1-12. ISSN~1754-8403. Available from: https://dx.doi.org/10.1242/dmm.041319.

Detailed Information on Publication Record