To the top

Page Manager: Webmaster
Last update: 9/11/2012 3:13 PM

Tell a friend about this page
Print version

Targeting apoptosis-induc… - University of Gothenburg, Sweden Till startsida
Sitemap
To content Read more about how we use cookies on gu.se

Targeting apoptosis-inducing factor as a novel therapeutic strategy for preventing perinatal brain injury

Doctoral thesis
Authors Juan Rodriguez
Date of public defense 2020-02-06
Opponent at public defense Professor Nikolaus Plesnila
ISBN 978-91-7833-688-3; 978-91-7833-689-0
Publisher Göteborgs universitet
Publication year 2020
Published at Institute of Neuroscience and Physiology, Department of Clinical Neuroscience
Language en
Links hdl.handle.net/2077/62221
Keywords AIF, neonatal, mouse, hypoxia-ischemia, AIF/CypA complex, apoptosis, asphyxia, CHCHD4
Subject categories Neurosciences, Cell and Molecular Biology, Physiology

Abstract

Perinatal complications such as asphyxia can cause brain injuries that are often associated with subsequent neurological deficits. The mechanisms of perinatal brain injury are not fully understood, but mitochondria play a prominent role, not only due to their central function in metabolism, but also because many proteins with apoptosisrelated functions are located in the mitochondrion. Among these proteins, CHCHD4 and apoptosis-inducing factor (AIF) have already been shown to make important contributions to neuronal cell death upon hypoxia-ischemia (HI), but a better understanding of the mechanisms behind these processes is required for the development of improved treatments. By inducing HI in 9-day-old mice, leading to moderate brain injury, we studied these mechanisms from multiple perspectives. First, we determined the effect of chchd4 haploinsufficiency, and we showed that neonatal mice with this genotype experienced less brain damage due to reduced translocation of AIF and Cytochrome c from the mitochondrion. Second, we characterized the role of a newly discovered AIF isoform (AIF2), which is only expressed in the brain and the functions of which are unknown. By using Aif2 knockout mice, we showed that under physiological conditions there is an increase in Aif1 expression (the ubiquitously expressed isoform) due to a compensatory effect of loss of Aif2 expression. As a result, these mice showed a higher degree of brain damage after HI and were more vulnerable to oxidative stress. Third, we used another transgenic mouse in which Aif was overexpressed by knocking in a proviral insertion of Aif, leading to an increased expression of Aif1 without affecting the expression of Aif2. This mouse also showed a higher degree of brain damage and higher levels of oxidative stress. Finally, we used a peptide designed to block the apoptotic function of AIF. The results in young mice showed that the neuroprotective effect of the peptide was greater in male mice than in female mice. In summary, this PhD project has opened new perspectives in the comprehension of the mechanisms by which CHCHD4 and AIF are crucial proteins for brain damage after HI, and it has showed that AIF is a promising therapeutic target for improving outcome after perinatal brain injury.

Page Manager: Webmaster|Last update: 9/11/2012
Share:

The University of Gothenburg uses cookies to provide you with the best possible user experience. By continuing on this website, you approve of our use of cookies.  What are cookies?