Project: The PrPC / PDK1 / TACE signaling axis at the cross-road of several aggregate-prone protein-associated neurodegenerative diseases
Alzheimer’s (AD), prion, Parkinson’s (PD) diseases, Amyotrophic Lateral Sclerosis (ALS), Spinocerebellar Ataxia type 1 (SCA1) and Frontotemporal Dementia (FTD) are neurodegenerative diseases characterized by distinct etiologies and pathophysiological features. Although each disease displays specific clinical manifestations, they may share common pathogenic cascades. Combining in vitro and in vivo approaches, we provided evidence for deregulation of the cellular prion protein (PrPC)/PDK1/TACE/TNFalpha Receptors signaling axis in both prion diseases and AD (Nat.Med. 2013). Overactivation of this cascade by pathogenic prions PrPSc or amyloid Abeta peptides amplifies PrPSc or Abeta productions and renders diseased neurons highly sensitive to TNFalpha. PrPC silencing or PDK1 inhibition mitigate both diseases. PrPC is also suspected to act as a sensor for various disease-associated aggregate-prone proteins. PrPC interaction with such proteins - alpha-synuclein (PD), SOD1 mutants (ALS), ataxin1 (SCA1), Tau/TDP43 (FTD) - would deviate PrPC signaling function and transduce toxic signals for neurons, but also enable their spreading in the nervous system. Our main goal is to assess whether PrPC-dependent overactivation of the PDK1/TACE/TNFR pathway contributes to neuroinflammation (WP1), accumulation (WP2) and spreading (WP3) of all these aggregate-prone proteins and thereby represents a therapeutic target (WP4) to combat aggregate-prone protein-associated neurodegenerative pathologies.
| Acronym | PrPC&PDK1 (Reference Number: JPND_CD_FP-688-009) |
| Duration | 01/01/2015 - 01/01/2018 |
| Project Topic | Neurodegenerative disease |
| Website | visit project website |
| Network | JPND |
| Call | A call for European research projects for cross-disease analysis of pathways related to neurodegenerative diseases |
Project partner
| Number | Name | Role | Country |
|---|---|---|---|
| 1 | University Paris Descartes - Inserm UMR-S 1124 | Coordinator | France |
| 2 | McGill University | Partner | Canada |
| 3 | KU Leuven | Partner | Belgium |
| 4 | Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE). Standort Tübingen | Partner | Germany |
| 5 | University of Sherbrooke | Partner | Canada |
| 6 | University of Oslo | Partner | Norway |