Understanding the neurospecificity of Prion protein signaling
Benoit Schneider1, Mathea Pietri1, Elodie Pradines1, Damien Loubet1, jean-Marie. Launay2, Odile Kellermann1, Sophie Mouillet-Richard1
1
INSERM U747, Paris Descartes University, 75006 Paris, France, 2Hopital Lariboisiere, 75009 Paris, France and Pharma Research Department, F. Hoffmann-La-Roche Ltd., CH-4070, Basel, Switzerland
TABLE OF CONTENTS
- 1. Abstract
- 2. Introduction
- 3. PrPC requirement for PrPSc-associated neurotoxicity
- 4. On the roads to signaling function : PrPC ligands, copper binding, knock-out and crosslinking
- 4.1. Insight from PrPC partners
- 4.2. Copper binding and cleavage
- 4.3. The knock-out approach
- 4.4. The crosslinking paradigm
- 5. PrPC signaling in neurons : a combination of ubiquitous and neurospecific effectors and pathways
- 5.1. NADPH oxidase activation, Reactive Oxygen Species production and redox equilibrium
- 5.2. ERK1/2 MAP Kinases, cell survival and homeostasis
- 5.3. The CREB Transcription factor
- 6. Neuronal specificity of PrPC signaling
- 6.1. Neuronal specificity of PrPC signaling : a matter of isoforms?
- 6.2. The PrPC -Caveolin-Fyn signaling platform
- 6.3. Linking PrPC signaling to synaptic plasticity : MMP-9 and beta-dystroglycan
- 6.4. PrPC and neuromodulation: TACE-dependent TNF-alpha shedding and bioamine metabolism
- 6.5. The interaction with TNAP : physiological implications
- 6.6. From effectors to functions : neuroprotection, neurite outgrowth and plasticity, myelin maintenance.
- 6.7. PrPC and copper
- 6.8. Calcium homeostasis
- 6.9. The GPCR connection
- 7. PrPScneurotoxicity : evidence for a subversion of PrP signaling
- 7.1. Prion-induced neurotoxicity : a loss of neuroprotective signals?
- 7.2. Evidence towards the gain of function hypothesis
- 7.2.1. Can the gain-of-function hypothesis be tested in vivo?
- 7.2.2. Lessons from the Prion peptide PrP 106-126
- 7.2.3. The contribution of chronically-infected cells
- 8. Conclusions and future directions
- 9. Acknowledgements
- 10. References
1. ABSTRACT
The cellular prion protein PrPC is the normal counterpart of the scrapie prion protein PrPSc, the main component of the infectious agent of transmissible spongiform encephalopathies (TSEs). It is a ubiquitous cell-surface glycoprotein, abundantly expressed in neurons, which constitute the targets of TSE pathogenesis. The presence of PrPC at the surface of neurons is an absolute requirement for the development of prion diseases and corruption of PrPC function(s) within an infectious context emerges as a proximal cause for PrPSc-induced neurodegeneration. Experimental evidence gained over the past decade indicates that PrPC has the capacity to mobilize promiscuous signal transduction cascades that, notably, contribute to cell homeostasis. Beyond ubiquitous effectors, much data converge onto a neurospecificity of PrPC signaling, which may be the clue to neuronal cell demise in prion disorders. In this article, we highlight the requirement of PrPC for TSEs-associated neurodegeneration and review the current knowledge of PrPC-dependent signal transduction in neuronal cells and its implications for PrPSc-mediated neurotoxicity
