Group 2: Cellular determinants of neuroprotection

About

Among the cellular determinants of neurodegenerative processes observed in all neurodegenerative diseases, mitochondrial dysfunction, endoplasmic reticulum (ER) stress and alteration of the ER-mitochondria communication appeared as common tracks largely sustaining the maintenance of toxic events. Indeed, interactions between ER and mitochondria are altered in all neurodegenerative pathologies and numerous genetic diseases. The question of the role of the highly functionalized domains of interaction between ER and mitochondria, known as MAMs, is currently a hot topic. MAM are stabilized by proteic bridges and sequester numerous proteic assemblies, where focused Ca2+ exchanges are driven by IP3 receptors on ER and VDAC1/MCU complexes on mitochondrial membranes. In Alzheimer's disease (AD), for instance, presenilins are expressed in MAMs and Aβ toxicity affects ER–mitochondria contacts. The altered microtubule associated protein Tau has an impact on the ER stress and UPR response that seems dependent of the mutation and/or the oligomer status.

We have previously shown that agonists activating the sigma-1 receptor (S1R), a protein highly concentrated in MAMs, resulted in an effective neuroprotection in animal models of AD or amyotrophic lateral sclerosis (ALS). Based on expertise in neuropharmacology, molecular genetics and cellular biology, our team develops a global project targeting these cellular determinants of neurodegeneration with a particular focus on S1R as: (1) a prototypic chaperone enabling functional restoration of ER-mitochondria communication and (2) a target platform for the development of innovative candidate drugs, in the tracks of Blarcamesine or Pridopidine, developed in AD, Huntington's disease and ALS.

Our team strategy, summarized in the following scheme, is developed in 4 complementary lines.

groupe2

Project 1. Communication deficit between ER and mitochondria in neurodegenerative diseases: from pathophysiology to therapy (Group leader: Benjamin Delprat)

Project 2. Counteracting mitochondrial dysfunctions in neurodegenerative diseases (group leader: Jean-Charles Liévens)

Project 3: Pathophysiological ER stress response in Tauopathies (project leader: Mireille Rossel)

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

Group

Tangui Maurice, group leader, Director, MMDN

maurice

Research Director, CNRS

Contact: tangui.maurice(at)umontpellier.fr

Phone: + 33/04 67 14 32 91

Benjamin Delprat

benjamin

Research Fellow, Inserm

Contact: benjamin.delprat(at)inserm.fr

Phone: 04 67 14 36 23

Jean-Charles Lievens

jclievens

Research Fellow, CNRS

Contact:jean-charles.lievens(at)umontpellier.fr

Phone : 04 67 14 32 85

Cécilia Marelli

marelli

PH, CHU

Contact: c-marelli(at)chu-montpellier.fr

Phone: 04 67 14 42 70

Mireille Rossel

rossel

Lecturer, EPHE

Contact: mireille.rossel(at)umontpellier.fr / mireille.rossel(at)ephe.sorbonne.fr

Phone : 04 67 14 38 15

Sylvain Bartolami

bartolami

Doctor, Lecturer, University of Montpellier

Contact: sylvain.bartolami(at)univ-montp2.fr / sylvain.bartolami(at)umontpellier.fr

Aline Freyssin

freyssin

REST Project Manager

Contact:

Phone:

Jérome Sarniguet

silhouette h

Engineer, Inserm

Contact: jérome.sarniguet(at)inserm.fr

Phone: 04 67 14 38 15

Nicolas Cubedo

nico

Assistant Engineer, Inserm

Contact: nicolas.cubedo(at)umontpellier.fr

Phone: 04 67 14 38 15

Amandine Peyrel

peyrel

Engineer, CDD

Contact: amandine.peyrel(at)umontpellier.fr

Phone: 04 67 14 36 23

Morgane Denus

Denus

Engineer

Contact: morgane.denus(at)umontpellier.fr

Phone: 04 67 14 36 23

Elodie Richard

richard

Post-doctoral Fellow

Contact:

Phone :

Allison Carles

carles

Phd Student

Contact:

Phone:

Lucie Crouzier

crouzier

PhD Student

Contact: lucie.crouzier(at)umontpellier.fr

Phone: 04 67 14 36 23

Loic Mele

mele

PhD Student

Contact:

Phone :

References

  • Couly S, Allison C, Morgane D, Benigno-Anton L, Maschat F, Maurice T. Exposure of R6/2 mice in an enriched environment augments P42 therapy efficacy on Huntington's disease progression. Neuropharmacology. 2021 Mar 15;186:108467. doi: 10.1016/j.neuropharm.2021.108467.
  • Lee PT*, Liévens JC*, Wang SM*, Chuang JY, Wu HE, Chang WC, Maurice T, Su TP. Sigma-1 receptor chaperones rescue nucleocytoplasmic transport deficit seen in ALS. Nat Commun. 2020 Nov 4;11(1):5580. doi: 10.1038/s41467-020-19396-3.
  • Crouzier L, Couly S, Roques C, Peter C, Belkhiter R, Arguel Jacquemin M, Bonetto A, Delprat B, Maurice T. Sigma-1 (σ1) receptor activity is necessary for physiological brain plasticity in mice. Eur Neuropsychopharmacol. 2020 Sep 3:S0924-977X(20)30260-1. doi: 10.1016/j.euroneuro.2020.08.010.
  • Barbereau C, Yehya A, Silhol M, Cubedo N, Verdier JM, Maurice T, Rossel M. Neuroprotective Brain-Derived Neurotrophic Factor signaling in the TAU-P301L tauopathy zebrafish model. Pharmacol Res. 2020 May 14:104865. doi: 10.1016/j.phrs.2020.104865.
  • Couly S, Khalil B, Viguier V, Roussel J, Maurice T, Liévens JC. Sigma-1 receptor is a key genetic modulator in amyotrophic lateral sclerosis. Hum Mol Genet. 2020 Mar 13;29(4):529-540. doi: 10.1093/hmg/ddz267.