The synergistic GIT2-RXFP3 system in the brain and its importance in age-related disorders
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1
University of Antwerp VIB, VIB-DMG, Belgium
Aging is the most important risk factor for developing neurodegenerative disorders (ND), such as Alzheimer’s disease. Furthermore, pathophysiological aging shares many common features with neurodegenerative processes, including mitochondrial/somatic DNA damage caused by oxidative stress, disruption of glucose metabolism and progressive loss of cellular stress resistance. This accumulation of cellular damage ultimately results in systemic dysfunction and eventual death. Given the similarities between aging and ND etiology, an enhanced appreciation of molecular aging pathomechanisms would significantly improve our ability to diagnose and/or treat the early stages of neurodegeneration. To address this, we identified GIT2 (G protein-coupled receptor kinase interacting protein 2) as a ‘hub’ protein that helps orchestrate the aging process. Hub proteins bridge multiple signaling pathways to coordinate multisystem processes such as aging or somatic metabolism. GIT2 is a known G protein-coupled receptor (GPCR) interacting protein and is known to be involved in both oxidative stress response and DNA damage repair processes. While GIT2 potentially presents itself as an important therapeutic target, GIT2 is considered as a non-canonical drug target. It is therefore important to identify proteins that can regulate GIT2 functions in order to gain control over the pathophysiological aging process with the potential to treat age-related disorders, such as neurodegeneration. Analyses of GIT2 knockout (GIT2KO) mice have led to the identification of a potential modulator of GIT2 functions: the relaxin family peptide receptor 3 (RXFP3). RXFP3 is a class A GPCR protein that was found to be consistently downregulated in GIT2KO mice and demonstrated several functional synergies with GIT2, including regulation of glucose metabolism and oxidative stress responsiveness. We generated in vitro RXFP3 constitutive cellular signaling signatures by progressive expression elevation followed by mass spectrometry-based analysis of the resultant cellular proteomic changes. We subsequently found strong evidence for a functional synergy between RXFP3 and GIT2 with respect to their shared roles in DNA damage repair, oxidative stress responsiveness, cell cycle arrest control and glucose metabolism functionalities. Further evidence supporting the existence of a synergisitic GIT2-RXFP3 system was provided by the demonstration of a physical interaction between both proteins as well as an RXFP3-dependent regulation of GIT2 expression. In conclusion, we propose that through a rational regulation of the RXFP3-GIT2 system new therapeutic strategies may be developed for neurodegenerative disorders.
Short comment
Aging is the strongest risk factor for developing neurodegenerative disorders, like Alzheimer’s disease. Many synergies exist between aging-related processes and the development of these disorders, suggesting that they interconnect. We have identified GIT2 as a potential aging regulator, modulating stress resistance, metabolism and DNA repair mechanisms, hallmarks of aging and neurodegeneration. Being able to control GIT2 functions may represent an important objective for both aging and neurodegenerative research. Hence, we identified RXFP3 as a potential GIT2 regulator, showing strong functional synergy and comparable expression patterns to GIT2. We propose that the GIT2-RXFP3 interaction may be important in regulating age-related neurodegeneration.
Résumé en français:
Le vieillissement est le principal facteur de risque pour le développement de maladies neurodégénératives, telles que la maladie d’Alzheimer. Les nombreuses synergies entre les processus de vieillissement et la survenue de ces maladies suggèrent l’existence d’une interconnexion. Nous avons identifié la protéine GIT2 comme un régulateur de vieillissement potentiel modulant la résistance au stress, le métabolisme et les mécanismes de réparation de l’ADN, trois processus atteints au cours du vieillissement et de la neurodégénérescence. Le contrôle potentiel des fonctions de la GIT2 pourrait donc constituer un objectif majeur pour la recherche sur le vieillissement et la neurodégénérescence. Nous avons identifié le gène RXFP3 comme régulateur potentiel de la GIT2, présentant une forte synergie fonctionnelle et des modèles d’expression comparables à la GIT2. Nous suggérons que l’interconnexion GIT2-RXFP3 est importante pour la régulation de la neurodégénérescence liée au vieillissement.
Samenvatting in het Nederlands:
Het verouderen is de belangrijkste factor in het ontwikkelen van neurodegeneratieve ziektes, zoals bv de ziekte van Alzheimer. Het dikwijls samenvallen van de verouderingsprocessen en het voorkomen van deze ziekten suggereren dat er een verband bestaat. Wij hebben de proteïne GIT2 geïdentificeerd als een mogelijke regulator die weerstand tegen stress, het metabolisme en de herstelmechanismen voor het DNA moduleert, drie processen die aangetast worden tijdens het verouderen en de neurodegeneratie. De potentiële controle van de functies van het GIT2 zou dus een belangrijk doel kunnen worden in het onderzoek naar veroudering en de neurodegeneratie. We identificeerden het gen RXFP3 als mogelijke regulator van het GIT2. Wij suggereren dat het verband tussen GIT2-RXFP3 belangrijk is voor de regulering van de neurodegeneratie gelinkt aan de veroudering.
Acknowledgements
This work was carried out with the support of the FWO Odysseus Research Program.
Keywords:
RXFP3,
GIT2,
Aging,
neurodegeneration,
GPCR
Conference:
6th Belgian Brain Congress, MONS, Belgium, 8 Oct - 8 Oct, 2016.
Presentation Type:
Poster Presentation
Topic:
Brain and brain diseases: between heredity and environment
Citation:
Van Gastel
J,
Janssens
J,
Etienne
H,
Azmi
A and
Maudsley
S
(2016). The synergistic GIT2-RXFP3 system in the brain and its importance in age-related disorders.
Conference Abstract:
6th Belgian Brain Congress.
doi: 10.3389/conf.fnagi.2016.03.00042
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Received:
29 Jun 2016;
Published Online:
05 Jul 2016.
*
Correspondence:
Miss. Jaana Van Gastel, University of Antwerp VIB, VIB-DMG, Antwerp, 2610, Belgium, Jaana.vangastel@molgen.vib-ua.be