GRADUAL ACCUMULATION OF OXIDATIVE STRESS AND ITS ASPECTS IN PRIMARY PORCINE FIBROBLASTS EXPRESSING MUTATED HUNTINGTIN

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985904%3A_____%2F18%3A00498986" target="_blank" >RIV/67985904:_____/18:00498986 - isvavai.cz</a>

Result on the web

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DOI - Digital Object Identifier

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Result language

angličtina

Original language name

GRADUAL ACCUMULATION OF OXIDATIVE STRESS AND ITS ASPECTS IN PRIMARY PORCINE FIBROBLASTS EXPRESSING MUTATED HUNTINGTIN

Original language description

Background Huntington´s disease (HD) is devastating neurodegenerative disorder caused by the mutation in huntingtin gene. One of the largest contributors to HD pathology represents oxidative stress, though the exact mechanism of its cause remains unclear. Molecular characterization of a unique porcine model of HD could serve for better understanding of the disease pathogenesis as well as for better evaluation of the therapeutic efficiency of preclinical studies on this large animal model.nAims In this study, we focused on the investigation of molecular and cellular features of fibroblasts isolated from transgenic minipigs expressing N-terminal part of human mutated huntingtin (TgHD) and the wild type (WT) siblings at different age, pre-symptomatic 24–36 months old and with starting behavioural symptoms at the age of 48 months.nMethods We investigated the levels of oxidative stress, the expression of oxidative stress related genes, proliferation capacity along with the expression of cyclin B1 and D1 proteins, cellular permeability, as well as nuclear and mitochondrial DNA damage in these cells.nResults TgHD fibroblasts isolated from 48 months old animals showed elevated levels of oxidative stress, overexpression of SOD2 gene, encoding a key mitochondria antioxidant, and NEIL3 gene, encoding DNA glycosylase involved in replication associated repair of DNA damaged by oxidative stress. These cells also displayed aberrant proliferation capacity and permeability. We further demonstrated preceded increased level of nuclear DNA damage in TgHD fibroblasts (isolated from 24–36 months old animals) indicating earlier aging of these cells.nConclusions Our results suggest the age of 48 months of TgHD minipig model to be a breakpoint in developing molecular phenotype of HD along with changes in behaviour. Furthermore, this work proposes TgHD minipigs as a suitable large animal model for studying molecular mechanisms occurring gradually in HD pathophysiology with age.n

Czech name

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Czech description

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Type

O - Miscellaneous

CEP classification

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OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

<a href="/en/project/LO1609" target="_blank" >LO1609: Models of the Serious Human Diseases: Traumatic Spinal Cord Injury, Huntington’s Disease, Melanoma and Infertility</a><br>

Continuities

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

Publication year

2018

Confidentiality

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