JNK Contributes to Hif-1α Regulation in Hypoxic Neurons

Xanthi Antoniou,Alessandra Sclip,Cristina Ploia,Gautier Moroy,Tiziana Borsello,Alessio Colombo

doi:10.3390/molecules15010114

Xanthi Antoniou, Alessandra Sclip + Show 4 more

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https://doi.org/10.3390/molecules15010114

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Abstract

Hypoxia is an established factor of neurodegeneration. Nowadays, attention is directed at understanding how alterations in the expression of stress-related signaling proteins contribute to age dependent neuronal vulnerability to injury. The purpose of this study was to investigate how Hif-1α, a major neuroprotective factor, and JNK signaling, a key pathway in neurodegeneration, relate to hypoxic injury in young (6DIV) and adult (12DIV) neurons. We could show that in young neurons as compared to mature ones, the protective factor Hif-1α is more induced while the stress protein phospho-JNK displays lower basal levels. Indeed, changes in the expression levels of these proteins correlated with increased vulnerability of adult neurons to hypoxic injury. Furthermore, we describe for the first time that treatment with the D-JNKI1, a JNK-inhibiting peptide, rescues adult hypoxic neurons from death and contributes to Hif-1α upregulation, probably via a direct interaction with the Hif-1α protein.

Highlights

Hypoxia describes a pathological state where the brain or part of it is deprived of an adequate oxygen supply; such a situation can occur in acute or chronic brain injuries.Understanding the molecular mechanisms that render adult neurons, as opposed to young ones, more vulnerable to hypoxia is crucial to our understanding of brain injuries
We investigated the role of Jun N-terminal kinase (JNK) signaling in the regulation of Hypoxia inducible transcription factor 1-α (Hif-1α) in young and adult neurons after hypoxic injury
Since Hif-1α has a JNK binding domain (JBD) and D-JNKI1 prevents hypoxia-induced neuronal death we investigated whether D-JNKI1 affects Hif-1α expression

Summary

Introduction

Understanding the molecular mechanisms that render adult neurons, as opposed to young ones, more vulnerable to hypoxia is crucial to our understanding of brain injuries. Adult neurons are more vulnerable to hypoxia due to several factors, including a decreased ATP availability and alterations of the NMDA receptors system [1]. Evidence exist that neuronal specific genes (as opposed to other brain cells) are markedly downregulated with increased age, and this decrease is independent of neuronal loss [3,4]. Hypoxia inducible transcription factor 1-α (Hif-1α) is a crucial neuroprotective factor induced in conditions of reduced oxygen supply. Hif-1α was shown to be involved in a number of neurodegenerative disorders and its expression is decreased in adult mice brains, as well as in other tissues and cells [6,7]. The pathways mediating Hif-1α are not fully characterised posttranslational modifications including ubiquitination, SUMOylation and phosphorylation were all shown to participate in Hif-1 regulation [10,11]

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