COEN Projects

Research projects selected during COEN calls for projects

As members of a center of excellence, LiCEND teams have submitted research projects application to the COEN calls for projects.

Two projects have been selected during the Pathfinder II (2015) and Pathfinder III (2017) calls for projects.

Principal Investigator: Sébastien Hébert (Université Laval, Québec, Canada),
Collaborators:   Jean-Charles Lambert (UMR1167, Lille, France); Luc Buée (UMR-S-1172, Lille, France)

Project context and objective :

Investigation of the genetic risk factors by Genetic Wild Association Studies (GWAS) has allowed the identification of genetic loci associated to the Alzheimer disease (AD). As such, these findings provide a glimpse into the potential cause(s) of AD. However, this vast pool of data needs to be filtered in order to identify the real culprit(s) of disease. Perhaps the greatest challenge in the post-GWAS era of Alzheimer’s disease (AD) is to understand the functional consequences of identified loci. Until now, GWAS analyses have identified 29 loci, containing 217 genes, genetically associated with AD. However, no gene is clearly pinpointed as being a culprit, and additional strategies are required to narrow down the list of candidates. microRNAs are small endogenous noncoding RNAs that function to repress protein output, and have been implicated in neurodegenerative disease. Recently, the project team has identified a number of SNPs in the APP gene affecting microRNA binding, potentially leading to increased risk for AD. The team’s unpublished observations suggest that several AD-associated polymorphisms abrogate microRNA function. The team is now aiming to explore in detail the relationship between GWAS data and microRNA. Overall, the project aim to uncover unprecedented roles of AD-associated loci. This will help understand the cause(s) of sporadic AD, and open the door to novel biomarkers and therapeutic avenues.

Principal Investigator : David Devos (UMR-1171, Lille, France),
Collaborators:   Alexander Storch (DZNE Rostock University Medical Center, Rostock, Allemagne), Nicola Pavese (NIHR Newcastle Dementia Biomedical Centre, Newcastle Upon Tyne, Royaume Uni)

Project context and objective 

A new discovered form of programmed cell death, Ferroptosis seems to be crucial in neurodegenerative diseases.

 The project team has been the first to demonstrate the role of ferroptosis in the Parkinson disease. Since then, implication of Ferroptosis has also been revealed in Amyotrophic Lateral Sclerosis and Alzheimer disease.
Ferroptosis has been first described in 2012 during therapeutic investigations on in breast cancer (RAS mutation). Some pro-ferroptosis molecules are currently developed against cancer cells and some anti-ferroptic drugs are under development in neurodegenerative diseases. The main ferroptosis physiological triggers identified (hypoxia, glutamate, calcium, pro-oxidants, pesticides, genetic mutations…) are well known to play a major role in neurodegenerative disease progression. Involved molecular mechanisms for triggering ferroptosis are actively investigated and new finding are regularly published. Those researches open tremendous therapeutic possibilities on a short term. In our team, it appears crucial to demonstrate that interaction between ferroptosis and synucleinopathy (major protein alteration in PD) exist at different levels. Both phenomena are related with iron; α-synuclein is involved in cellular iron balance with its aggregation state modified by the presence of iron, and ferroptosis is an iron dependent process. Thus this project proposes to elucidate how the modifications to α-synuclein observed in Parkinson’s disease can promote ferroptosis to exacerbate the spreading of neuron death throughout the brain. Short term outcomes expected from this work are innovative therapeutic strategies based upon recently generated anti-ferroptotic drugs.

AGENDA

  1. LiCEND Summer school 2019 : Experimental Models for Neurodegenerative Disease: From Cells to Model Organisms

    2 July / 5 July

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