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 in many genetic diseases. The role of highly functionalized interaction domains between the ER and mitochondria, 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 the mitochondrial membranes. In Alzheimer’s disease (AD), for example, presenilins are expressed at MAMs, andAβ toxicity affects ER-mitochondrial contacts. Tau protein associated with altered microtubules impacts ER stress and the UPR, which appears to depend on the mutation and/or oligomeric status.
We have previously shown 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 that enables the functional restoration of ER-mitochondrial communication and (2) a target platform for the development of innovative drug candidates, following in the footsteps of Blarcamesine and Pridopidine, which were developed for Alzheimer’s disease, Huntington’s disease, and ALS.
The team's strategy is structured around four complementary pillars.