ANR 2017 - DEMENTIA

Exploiting genetic biomarkers of neurodegenerative diseases for developing early diagnostic tests and possible treatments

Dementia is a general term for decline in mental ability and cognitive dysfunctions severe enough to interfere with everyday life. Dementia encompasses different but often overlapping pathologies including Alzheimer diseases (60-80% of the diagnosed cases) along with Parkinson’s, Pick’s (also known as frontotemporal degeneration, FTD) and Charcot’s diseases (also known as amyotrophic lateral sclerosis, ALS). These neurological disorders occur because nerve cells involved in cognitive functions undergo degeneration. There are currently no convenient, reliable clinical assays and therapeutic approaches to diagnose and treat dementia, which make them a societal issue of utmost importance. A breakthrough came in 2011 when scientists discovered a common genetic basis for two types of dementia, FTD (the second most common cause of early-onset dementia) and ALS. These two diseases, which display considerable pathological overlap, are so intertwined that they are now commonly referred to as FTD/ALS diseases. It was thus discovered that a defect in chromosome 9 (more precisely, in the open reading frame 72 of chromosome 9, so called C9orf72) is responsible for FTD/ALS diseases. This genetic aberration is characterized by the expansion of the hexanucleotide repeat GGGGCC, or d[G4C2], with an average of 2 repeats for healthy people while FTD/ALS patients carry up to thousand repeats. The G4C2-repeats thus represent a reliable genetic biomarker that could help clinicians diagnose FTD/ALS earlier. In this project, named DEMENTIA, we first describe the current state of knowledge on FTD/ALS diseases, from the mechanistic bases of the G4C2-mediated or -promoted neurotoxicity to the therapeutic strategies that are currently investigated to tackle this critical societal issue. We next exploit the wealth of data recently acquired on C9orf72 repeats, with a particular focus on the RNA r[G4C2] repeats that are more readily accessible in nerve cells, with a two-fold purpose: 1- to study precisely the secondary structures they might fold into (i.e., hairpin and/or quadruplexes) in order to decipher the conditions that govern their folding dynamics; we will then exploit these data to develop an in vitro fluorescent assays capable of detecting these structures from cell and RNA extracts for diagnosis purposes; and 2- to exploit this in vitro assay to identify new chemicals that could disrupt these higher-order structures (known to be responsible for neural injuries) to identify new drugs capable of curbing or reversing neurodegeneration, therefore addressing an unmet need for effective therapies to treat dementia. To this end, DEMENTIA relies on the complementarity of the people and the institutes involved (ICMUB at Dijon, Institut Curie at Orsay and IECB at Bordeaux) and is built on the firmly established expertise of the project’s partners, according to a two-way organization that makes it a low-risk, yet ambitious and resolutely interdisciplinary research program.