Gradual Phenotype Development in Huntington Disease Transgenic Minipig Model at 24 Months of Age

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985904%3A_____%2F18%3A00495752" target="_blank" >RIV/67985904:_____/18:00495752 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11310/18:10390009

Výsledek na webu

<a href="http://dx.doi.org/10.1159/000488592" target="_blank" >http://dx.doi.org/10.1159/000488592</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1159/000488592" target="_blank" >10.1159/000488592</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Gradual Phenotype Development in Huntington Disease Transgenic Minipig Model at 24 Months of Age

Popis výsledku v původním jazyce

Background: Huntington disease (HD) is an incurable neurodegenerative disease caused by the expansion of a polyglutamine sequence in a gene encoding the huntingtin (Htt) protein, which is expressed in almost all cells of the body. In addition to small animal models, new therapeutic approaches (including gene therapy) require large animal models as their large brains are a more realistic model for translational research. Objective: In this study, we describe phenotype development in transgenic minipigs (TgHD) expressing the N-terminal part of mutated human Htt at the age of 24 months. Methods: TgHD and wild-type littermates were compared. Western blot analysis and subcellular fractionation of different tissues was used to determine the fragmentation of Htt. Immunohistochemistry and optical analysis of coronal sections measuring aggregates, Htt expression, neuroinflammation, and myelination was applied. Furthermore, the expression of Golgi protein acyl-CoA binding domain containing 3 (ACBD3) was analyzed. Results: We found age-correlated Htt fragmentation in the brain. Among various tissues studied, the testes displayed the highest fragmentation, with Htt fragments detectable even in cell nuclei. Also, Golgi protein ACBD3 was upregulated in testes, which is in agreement with previously reported testicular degeneration in TgHD minipigs. Nevertheless, the TgHD-specific mutated Htt fragments were also present in the cytoplasm of striatum and cortex cells. Moreover, microglial cells were activated and myelination was slightly decreased, suggesting the development of a premanifest stage of neurodegeneration in TgHD minipigs. Conclusions: The gradual development of a neurodegenerative phenotype, accompanied with testicular degeneration, is observed in 24- month-old TgHD minipigs.

Název v anglickém jazyce

Gradual Phenotype Development in Huntington Disease Transgenic Minipig Model at 24 Months of Age

Popis výsledku anglicky

Background: Huntington disease (HD) is an incurable neurodegenerative disease caused by the expansion of a polyglutamine sequence in a gene encoding the huntingtin (Htt) protein, which is expressed in almost all cells of the body. In addition to small animal models, new therapeutic approaches (including gene therapy) require large animal models as their large brains are a more realistic model for translational research. Objective: In this study, we describe phenotype development in transgenic minipigs (TgHD) expressing the N-terminal part of mutated human Htt at the age of 24 months. Methods: TgHD and wild-type littermates were compared. Western blot analysis and subcellular fractionation of different tissues was used to determine the fragmentation of Htt. Immunohistochemistry and optical analysis of coronal sections measuring aggregates, Htt expression, neuroinflammation, and myelination was applied. Furthermore, the expression of Golgi protein acyl-CoA binding domain containing 3 (ACBD3) was analyzed. Results: We found age-correlated Htt fragmentation in the brain. Among various tissues studied, the testes displayed the highest fragmentation, with Htt fragments detectable even in cell nuclei. Also, Golgi protein ACBD3 was upregulated in testes, which is in agreement with previously reported testicular degeneration in TgHD minipigs. Nevertheless, the TgHD-specific mutated Htt fragments were also present in the cytoplasm of striatum and cortex cells. Moreover, microglial cells were activated and myelination was slightly decreased, suggesting the development of a premanifest stage of neurodegeneration in TgHD minipigs. Conclusions: The gradual development of a neurodegenerative phenotype, accompanied with testicular degeneration, is observed in 24- month-old TgHD minipigs.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

<a href="/cs/project/LO1609" target="_blank" >LO1609: Modely závažných lidských onemocnění: Traumatické poškození míchy, Huntingtonova choroba, melanom a neplodnost</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Neurodegenerative Diseases

ISSN

1660-2854

e-ISSN

—

Svazek periodika

18

Číslo periodika v rámci svazku

2-3

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

13

Strana od-do

107-119

Kód UT WoS článku

000442610700007

EID výsledku v databázi Scopus

2-s2.0-85048172018