NEURAGE

The pathogenesis of age-related neurodegenerative diseases, despite a tremendous increase in our knowledge, is still not well understood and these prevalent diseases crucially lack effective treatments. To address this hurdle, we aim to investigate a novel, previously unrecognized axis in the pathogenesis of age-related neurodegenerative diseases and to test new therapeutic strategies targeting this pathway. Based on solid data from our lab and others, we hypothesize that aging-induced global chromatin disorganization leads to the de-repression of transposable elements (TE) in neurons. The uncontrolled activation of TEs, particularly LINE-1 (L1) retrotransposons, can induce genomic instability and potentially neuroinflammation and gene expression dysregulation, thereby promoting neurodegeneration. We have recently shown in mice that oxidative-stress induced heterochromatin de-structuration and L1 de-repression initiate genomic instability and drive neurodegeneration. The activation of L1, the only autonomously active TEs in humans, could thus be a central player in neurodegenerative diseases. Full-length L1 encode two proteins, ORF1p, an RNA binding protein, and ORF2p, an endonuclease and a reverse transcriptase, critical for target site DNA cleavage and re-integration into the genome (retrotransposition). While it is plausible to argue that this axis might be a general mechanism common to all age- related neurodegenerative disorders, we focus here on dopaminergic neurodegeneration associated with Parkinson’s disease (PD), using human post-mortem dopaminergic neurons and tissues, human dopaminergic neurons in culture and models of PD. We believe that bringing together the backgrounds and methodological resources of two neuroscientists (coordinator and partner #1) and a chemical biologist (partner #2) will provide a unique interdisciplinary workforce to answer the questions raised, including the presence of age-related nuclear dysfunction and L1 de-repression in PD and the possibility of reversing nuclear dysfunction using small molecules developed by partner #2. These small molecules revert nuclear phenotypes associated with aging and are therefore ideal candidates to be evaluated, characterized and developed in this context. To answer these questions, we have formulated three objectives: (1) the identification of nuclear dysfunctions in PD, including L1 de-repression, (2) the establishment of an in vitro model of human dopaminergic premature ageing in order to study the molecular mechanisms at the origin of the pathogenic process initiated by age-related chromatin de-structuration and L1 depressing and (3) the evaluation of the effect of the small "anti-ageing" molecules in the model developed in (2) on chromatin organization, DNA damage and L1 regulation. This proposal is expected to deliver a unifying mechanism providing the fertile ground for the understanding of the age-related pathogenesis of PD and the development of new therapeutics.