Group 2

Cellular determinants of neuroprotection

Among the cellular determinants of neurodegenerative processes observed in all neurodegenerative diseases, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, andimpaired ER-mitochondrial communication have emerged as common events responsible for the persistence of toxicity. Interactions between the ER and mitochondria are impaired in all neurodegenerative disorders and many genetic diseases. The role of highly functionalized ER-mitochondria interaction domains, known as MAMs, is currently a major focus of research. MAMs are stabilized by protein bridges and sequester numerous protein complexes, where focal Ca2+ exchanges are facilitated by IP3 complexes on the ER and VDAC1/MCU on mitochondrial membranes. In Alzheimer’s disease (AD), for example, presenilins are expressed in MAMs, andAβ toxicity affects ER-mitochondria contacts. The tau protein associated with modified microtubules impacts ER stress and the UPR response, which appears to depend on the mutation and/or oligomeric status.

We have previously demonstrated that agonists that activate the sigma-1 receptor (S1R)—a protein highly concentrated in MAMs—provide effective neuroprotection in animal models of Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Drawing on expertise in neuropharmacology, molecular genetics, and cell biology, our team is developing a comprehensive project targeting these cellular determinants of neurodegeneration with a particular focus on S1R as (1) a prototype chaperone enabling the functional restoration of ER-mitochondria communication and (2) a target platform for the development of innovative drug candidates, following in the footsteps of Blarcamesine or Pridopidine, which have been developed for Alzheimer’s disease, Huntington’s disease, and ALS.

The team’s strategy, summarized in the following diagram, is structured around four complementary pillars.

Project 1. Communication Deficits Between the Endoplasmic Reticulum and Mitochondria in Neurodegenerative Diseases (Group Leader: Benjamin Delprat)

Project 2. Combating mitochondrial dysfunction in neurodegenerative diseases (Group Leader: Jean-Charles Liévens)

Project 3: The role of pathophysiological ER stress in tauopathies (Group Leader: Mireille Rossel)

Project 4: Drug development programs: S1R agonists, FENMs, and beyond (group leader: Tangui Maurice)