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Browsing by Subject "KEAP1/Nrf2-ARE pathway"

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  • Ahvenainen, Ella (2023)
    The developing human hindbrain and its role in neuronal pathogenesis have been relatively difficult to study for ethical reasons. By using the dual-SMAD inhibition and WNT signalling induction, a new method to culture brain organoids to resemble the human hindbrain has recently been established. In this study the new method has been used to detect the developing hindbrain’s response to flaviviral infection. Model virus used in this study is the Zika virus (ZIKV) which is known to alter the development of central nervous system and cause microcephalia. Pathogenic activity of the virus is measured by detecting the morphology of the organoids during infection as well as screening the organoids activation against oxidative stress, in a form of KEAP1/Nrf2-ARE pathway activation. Three different clones of ZIKV, which differ from each other by one amino acid in their non-structural protein 1 (NS1) gene, were used in the infections as well as two different time points of development. Controversially to previous findings on ZIKV infections to brain organoids, our findings show that developing hindbrain-like organoids do not change in shape or size during ZIKV infection. There are no differences in the lack of morphological changes between one-month olds or two months old organoids or between the different ZIKV clone infected organoids. The activation of the KEAP1/Nrf2-ARE pathway was measured by screening the two final products of the pathway, Nqo1 and HO-1. By screening the mRNA levels of these two genes, it showed that different ZIKV clones affect the activation of the KEAP1/Nrf2-ARE pathway in different levels at different times of development. Also, the expression of the same gene can be altered by the age of the organoids. Additionally, the expression of the two genes were different from each other at given time points and in response to the different clones. These findings suggest that the different isoforms of NS1 of ZIKV may alter the developing hindbrain’s response to oxidative stress. Findings also show that the time of the infection can additionally play a critical role to the ZIKV infection. The altered response to oxidative stress may contribute to microcephaly: the oxidation homeostasis of the developing hindbrain is modified, and apoptotic cell death can take place.