Control of GDNF expression by AD-related proteins and implications in neurodegenerative and neuromuscular diseases
-
1
Université catholique de Louvain, Institute of Neuroscience, Belgium
The physiological function of the Amyloid Precursor Protein (APP) remains poorly understood. APP has been extensively studied for its involvement in Alzheimer's disease (AD) since its amyloidogenic processing leads to the formation of beta-amyloid peptide (Aβ), the major constituent of senile plaques that are typical AD lesions.
We contributed to a more comprehensive picture of APP regulatory network and physiological function by showing that APP-dependent regulation of the Glial cell line-Derived Neutrophic Factor (GDNF) drives the process of neuronal and muscular maturation involved in neuromuscular junctions (NMJs) formation (1). APP function is likely to rely in important part mainly to the regulation of APP target genes expression. So far, the identity of genes regulated by APP is intense matter of debate and, in addition, these genes are often difficult to relate to the phenotype observed in APP-deficient mice. APP-dependent GDNF transcription appears as critical for the muscular phenotype observed in APP null transgenic mice (APP-/-).
Interestingly, our recent experiments indicated that Presenilins (PS) are also involved in the regulation of GDNF transcription. Presenilins-dependent γ-secretase activity generates the Aβ peptide and releases the APP intracellular domain (AICD), which was shown to be the transcriptionally active APP fragment. It is therefore of particular interest to understand the molecular mechanisms recruited by APP/PS to control the expression of GDNF, a neurotrophic factor fundamental for both central and peripheral nervous system (CNS, PNS), neuron survival and, importantly, altered in AD and amyotrophic lateral sclerosis (ALS). The goal of this study is to identify cross-disease pathways and evaluate the relevance of therapeutic approaches targeting the APP/PS/GDNF pathway.
Summary:
The major role of APP in the onset and progression of AD has been revealed almost three decades ago by the combination of genetic and biochemical approaches, leading to the amyloid cascade hypothesis. Nevertheless, APP and Presenilins (PS) physiological function(s) and how they relate to AD and other associated pathologies are not clearly understood. We recently showed that APP controls GDNF transcription and this has a pivotal role in the formation of NMJs. This is particularly relevant to APP function, because APP deficient mice show a neuromuscular phenotype. Pilot experiments indicated that GDNF expression is also directly controlled by PS activity. Knowing that GDNF is a major neurotrophic factor, involved in PNS and CNS neuron survival, and that GDNF has been suggested marker of AD, it is of particular relevance to understand how APP and PS control GDNF expression, and how these pathways are related to AD pathological process.
Résumé en Français:
La protéine précurseur du peptide amyloïde (APP) joue un rôle majeur dans l’apparition et le développement de la maladie d’Alzheimer. Cependant, les étapes menant à sa dérégulation et son rôle physiologique est encore très mal connu. Nous avons montré récemment que l’APP contrôlait la production d’un facteur capable de réguler l’expression de nos gènes (facteur de transcription), le GDNF. Ce facteur joue un rôle très important dans la formation des jonctions entre les neurones et les muscles et dans la survie des neurones du système nerveux central et périphérique. Le but de notre étude est de mieux comprendre comment l’APP régule le GDNF et si cette régulation est perturbée au cours de la maladie d’Alzheimer.
Samenvatting in het Nederlands:
Het voorloper proteïne van de amyloïde peptide (APP) speelt een belangrijke rol in het ontstaan en de verdere ontwikkeling van de ziekte van Alzheimer. Toch blijft veel onbekend over de verschillende stadia van zijn ontregeling en zijn fysiologische rol. Recent toonden we aan dat APP instaat voor de ontwikkeling van een factor die in staat is de uitdrukking van onze genen te regelen (transcriptie factor) GDNF genaamd. Deze factor speelt een zeer belangrijke rol in de verbindingen tussen neuronen en spieren en in het overleven van neuronen van het centrale en perifere zenuwstelsel. Het doel van onze studie is tot een beter begrip te komen hoe de APP het GDNF reguleert en of deze regulering verstoord wordt tijdens de ziekte van Alzheimer.
Acknowledgements
The authors are grateful to Bart de Strooper (Katholieke Universiteit Leuven, Leuven, Belgium) for the kind gift of mouse embryonic fibroblast cells. This work was supported by a grant from the Belgian Fonds National pour la Recherche Scientifique (to S.S.), by the S.A.O./F.R.A. Stichting voor Alzheimer Onderzoek/Foundation for Research on Alzheimer’s disease (to P.K.-C.), Interuniversity Attraction Pole Programme-Belgian Sate-Belgian Science Policy (IAP-P7/16 and IAP-P7/13 to J.-N.O., P.K.-C.),
References
Stanga S, Zanou N, Audouard E, Tasiaux B, Contino S, Vandermeulen G, René F, Loeffler JP, Clotman F, Gailly P, Dewachter I, Octave JN, Kienlen-Campard P: ‘APP-dependent glial cell line-derived neurotrophic factor gene expression drives neuromuscular junction formation.’ FASEB J. 2016 May; 30(5):1696-711. doi: 10.1096/fj.15-278739. Epub 2015 Dec 30.
Keywords:
Alzheimer's disease,
gene transcription,
Amyloid beta-Protein Precursor,
Presenilins,
Neuromuscular Diseases
Conference:
6th Belgian Brain Congress, MONS, Belgium, 8 Oct - 8 Oct, 2016.
Presentation Type:
Oral Presentation
Topic:
Brain and brain diseases: between heredity and environment
Citation:
Stanga
S,
Tasiaux
B,
Dewachter
I,
Octave
J and
Kienlen-Campard
P
(2016). Control of GDNF expression by AD-related proteins and implications in neurodegenerative and neuromuscular diseases.
Conference Abstract:
6th Belgian Brain Congress.
doi: 10.3389/conf.fnagi.2016.03.00075
Copyright:
The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers.
They are made available through the Frontiers publishing platform as a service to conference organizers and presenters.
The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated.
Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed.
For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions.
Received:
14 Jul 2016;
Published Online:
15 Jul 2016.
*
Correspondence:
PhD. Serena Stanga, Université catholique de Louvain, Institute of Neuroscience, Bruxelles, 1200, Belgium, serena.stanga@unito.it