Summary: From prion diseases to Alzheimer’s disease: convergence of neurodegeneration mechanisms

Although amyloid-based neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, prion diseases… display distinct etiologies and clinical manifestations, it is more and more suspected the occurrence of common mechanisms of neurodegeneration.

Starting from prion diseases, we uncovered a neurodegenerative signaling cascade that is common to prion and Alzheimer’s diseases. In this cascade, two kinases ROCK (for RhoA-associated kinases) and PDK1 (for 3-phosphoinositide-dependent kinase-1) provoke the neutralization of the neuroprotective α-secretase TACE (ADAM17). This amplifies the production of pathogenic prions PrP^Sc in prion diseases and beta-amyloid (Aβ) peptides in Alzheimer’s disease and renders diseased neurons highly vulnerable to TNFα injury.

We recently showed that the deregulation of the PDK1-TACE pathway by PrP^Sc is also at the root of Aβ overproduction in prion diseases. Accumulated Aβ can deposit and form plaques in the brain of prion-infected mice, but only when a seed of trimers of Aβ is co-transmitted with PrP^Sc, which introduces trimers of Aβ as seeding and replicating entities. The consequence of brain Aβ deposition is an anticipated death of prion-infected mice because of the onset of a mixed PrP^Sc/Aβ pathology.

This presentation will detail the mechanisms sustaining deregulation of the ROCK-PDK1-TACE pathway in prion and Alzheimer’s diseases and define whether targeting the ROCK/PDK1 kinases duo would be a novel therapeutic option for both prion and Alzheimer’s diseases and possibly other amyloid-based neurodegenerative diseases.

Short Biography

Benoit Schneider is currently head of the team “Stem Cells, Signaling and Prions” at the Université de Paris, INSERM Unit UMR-S1124. He attended the Ecole Normale Supérieure in Cachan between 1993 and 1997, where he obtained the “agrégation” of Biochemistry and a Master 2 in Molecular and Cell Biology (University Pierre-et-Marie Curie, Paris). He obtained a Ph.D. in biochemistry, enzymology, and structural biology (University Pierre-et-Marie Curie, Paris) in 2001 at the Pasteur Institute (Paris). He then joined the laboratory of Odile Kellermann (CNRS, Villejuif) as a post-doctoral fellow to work on neuronal differentiation and prions. He subsequently got a position as Chargé de Recherche in 2003 in the CNRS. He defended an HDR in 2007 and became Professor at the Ecole Polytechnique dispensing lectures in biochemistry and toxicology. In 2014, he was promoted to Directeur de Recherche in the CNRS. The main research axis his team develops focuses on the molecular bases of neurodegeneration in prion and Alzheimer’s diseases. His research is supported by national (ANR) and international (European Joint Program on Neurodegenerative Diseases) grants, as well as subventions from foundations (Vaincre Alzheimer). He is the author of 70 articles plus 3 patents.

To join the Zoom meeting:

https://u-paris.zoom.us/j/84844810830?pwd=SGZKNzdNb0lUa0dYS2hoMEx0M2pwdz09

ID of the meeting : 848 4481 0830

Code : 412124