• No results found

Targeting Apoptosis-Inducing Factor as a Novel Therapeutic Strategy for Preventing Perinatal Brain Injury

N/A
N/A
Protected

Academic year: 2021

Share "Targeting Apoptosis-Inducing Factor as a Novel Therapeutic Strategy for Preventing Perinatal Brain Injury"

Copied!
2
0
0

Loading.... (view fulltext now)

Full text

(1)

Göteborg, 2020

SAHLGRENSKA AKADEMIN

Targeting Apoptosis-Inducing Factor as a Novel Therapeutic Strategy for Preventing Perinatal

Brain Injury

Akademisk avhandling

Som för avläggande av medicine doktorsexamen vid Sahlgrenska akademin, Göteborgs universitet kommer att offentligen försvaras i hörsal Karl Isaksson,

Medicinaregatan 16A, Göteborg, den 6 februari 2020, klockan 13.00 av Juan Rodríguez

Fakultetsopponent:

Professor Nikolaus Plesnila

Ludwig-Maximilians-University, Munich, Germany

Avhandlingen baseras på följande delarbeten

I. Sun Y, Li T, Xie C, Xu Y, Zhou K, Rodriguez J, Han W, Wang X, Kroemer G, Modjtahedi N, Blomgren K, Zhu C. "Haploinsufficiency in the mitochondrial protein CHCHD4 reduces brain injury in a mouse model of neonatal hypoxia-ischemia." Cell Death & Disease 2017;

doi:10.1038/cddis.2017.196

II. Rodriguez J, Zhang Y, Li T, Xie C, Sun Y, Xu Y, Zhou K, Huo K, Wang Y, Wang X, Andersson D, Ståhlberg A, Xing Q, Mallard C, Hagberg H, Modjtahedi N, Kroemer G, Blomgren K, Zhu C. “Lack of the brain-specific isoform of apoptosis-inducing factor aggravates cerebral damage in a model of neonatal hypoxia–ischemia.” Cell Death & Disease 2018; doi:10.1038/s41419-018-1250-1

III. Li T, Li K, Zhang S, Wang Y, Xu Y, Cronin S, Sun Y, Zhang Y, Xie C, Rodriguez J, Zhou K, Hagberg H, Mallard C, Wang X, Penninger J, Kroemer G, Blomgren K, Zhu C. “Overexpression of apoptosis inducing factor aggravates hypoxic-ischemic brain injury in neonatal mice.” Submitted 2019 IV. Rodriguez J, Xie C, Li T, Sun Y, Xu Y, Li K, Wang Y, Zhou K, Mallard C, Hagberg H, Doti N, Wang

X, Zhu C. “Inhibiting the interaction between apoptosis inducing factor and cyclophilin A prevents brain injury in neonatal mice after hypoxia-ischemia.” Submitted 2019

INSTITUTIONEN FÖR NEUROVETENSKAP OCH

FYSIOLOGI

(2)

Göteborg, 2020

ISBN 978-91-7833-688-3 (TRYCK) ISBN 978-91-7833-689-0 (PDF)

http://hdl.handle.net/2077/62221

Targeting Apoptosis-Inducing Factor as a Novel Therapeutic Strategy for Preventing Perinatal

Brain Injury

Juan Rodríguez

Department of Clinical Neuroscience at Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sweden, 2020

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 apoptosis- related 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.

Keywords: AIF, AIF/CypA complex, apoptosis, asphyxia, CHCHD4, hypoxia- ischemia, mouse, neonatal

References

Related documents

We demonstrate constitutive expression of all Toll-like receptors (TLRs), a sub-family of pathogen recognition receptors, in the neonatal CNS and active regulation of TLRs 1, 2, 5,

The aim of the thesis was to investigate (1) the role of astrocyte activation and reactive gliosis in neonatal hypoxic-ischemic (HI) brain injury, (2) the role

the reduction in tissue loss, the injury to MBP and neurofilaments was also attenuated in MMP-9 deficient animals, which is similar to studies of focal cerebral ischemia in

Perinatal brain injury, as a result of hypoxia-ischemia (HI) or infection/HI, is a major cause of acute mortality and neurological morbidity in infants and children. The mechanisms

The aims were to investigate (a) the novel inflammatory marker galectin-3 that affects accumulation, apoptosis and activation of inflammatory cells and (b) free radical formation

Among these proteins, coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4) and apoptosis-inducing factor (AIF) have already been shown to make

Taken together, this study showed that excessive AIF (specifically the AIF1 isoform) does not cause obvious phenotypic changes or alterations in the physiological functions, but

 The incidence and the extent of the most common altered proteins seen in the aging brain (HP, Aβ, αS, and TDP43) in a well characterized, large, cohort of cognitively