NEUROPROTEOMICS AND SIGNALING OF NEUROLOGICAL AND PSYCHIATRIC DISORDERS
Department: Neurosciences - Research axis: GPCR signaling

Research subject

The team deciphers protein networks interacting with several receptors and the plasma membrane transporter of serotonin, a major neurotransmitter of the central nervous system implicated in numerous physiological and pathological processes. We pay particular attention on the role these networks in synaptic transmission and plasticity, neuronal survival, mood and cognition, using a combination of proteomic, biochemical, electrophysiological and behavioural approaches. Among the receptor subtypes activated by serotonin, our studies mainly focus on 5-HT2A, 5-HT4 and 5-HT6 receptors.

The 5-HT2A receptor, predominantly expressed in prefrontal cortex, is a major target of second-generation antipsychotics such as clozapine, olanzapine and risperidone, and of psychedelic hallucinogens, such as LSD. This receptor is involved in the control of nociception and contributes to the analgesic effects of antidepressants. Our goal is to identify molecular substrates of the psychoactive effects of hallucinogens thanks to quantitative phosphoproteomics strategies and to characterize the impact of 5-HT2A receptors upon glutamatergic synaptic transmission and synaptic plasticity in prefrontal cortex. We also participate in the development of small molecule inhibitors of the interactions between 5-HT2A receptors and their associated protein networks as analgesic agents for the treatment of neuropathic pain.

Activation of 5-HT4 receptors induces pro-cognitive effects. 5-HT4 receptor expression and activation also promote non-amyloidogenic cleavage of Amyloid Precursor Protein (APP), and thereby prevent accumulation of toxic amyloid peptide in senile plaques. This receptor is a potential target to slow the progression of Alzheimer’s disease and to reduce cognitive symptoms. We investigate signalling mechanisms underlying non-amyloidogenic APP processing elicited by the receptor and study the impact of receptor expression and activation on disease progression in preclinical models of Alzheimer’s disease.

The 5-HT6 receptor plays an essential role in cognition and 5-HT6 receptor blockade has emerged as one promising strategy for the treatment of cognitive deficits of both Alzheimer’s disease and schizophrenia. We look for signalling pathways engaged by 5-HT6 receptors contributing to its regulation of neuronal differentiation, synaptogenesis and cognition. These pathways constitute potential therapeutic targets to reduce cognitive decline in both dementia and psychoses.

The team also looks for biomarkers of neurological disorders (Alzheimer’s disease, multiple sclerosis), by means of high-resolution peptide profiling of cerebrospinal fluid samples from patients and characterization of proteins secreted by various cell populations of the central nervous system (neurons, astrocytes and oligodendrocytes) under control and pathological (inflammation, apoptosis) conditions.

 

img.marin.200

Team

Team leader

Philippe Marin
DR1, CNRS


  IGF Sud 221

  04 34 35 92 42

 

Staff

Carine Becamel
MCF, UM


  IGF Sud 224

  04 34 35 92 15

 

Joel Bockaert
PU, UM


  IGF Sud 215

  04 34 35 92 42

 

Séverine Chaumont-Dubel
MCF, UM


  IGF Sud 029

  04 34 35 92 05

 

Sylvie Claeysen
CRCN, Inserm


  IGF Sud 224

  04 34 35 92 15

 

Alexandre Derré
Master 2, CNRS


  IGF Sud 224

  04 34 35 92 15

 

Emilie Doucet
Post-doctorant(e), UM


  IGF Sud 224

  04 34 35 92 15

 

Lucile Du Trieu
Doctorant(e), CNRS


  IGF sud 026

  04 34 35 92 06

 

Vincent Dupuy
Doctorant(e), UM


  IGF Sud 026

  04 34 35 92 06

 

Karolina Foksa
Master 2, CNRS


  IGF Sud 216

  04 34 35 92 13

 

Amos Fumagalli
Doctorant(e), CNRS


  IGF Sud R26

  04 34 35 92 06

 

Bérénice Hatat
Doctorant(e), CNRS


  IGF Sud 224

  04 34 35 92 15

 

Geoffrey Hinsinger
Stagiaire, CNRS


  IGF Sud R26

  04 34 35 92 06

 

Caroline Ismeurt
Doctorant(e), UM


  IGF Sud 224

  04 34 35 92 15

 

Simon Nicot
IR CDD, CNRS


  IGF Sud 204

  04 34 35 92 15

 

Hugo Payan
Doctorant(e), UM


  IGF Sud 224

  04 34 35 92 15

 

Camille Pujol
Doctorant(e), UM


  IGF Sud 026

  04 34 35 92 06

 

Angelina Rogliardo
Doctorant(e), CNRS


  IGF Sud 224

  04 34 35 92 15

 

Éric Thouvenot
PU-PH, CHU Nîmes


  IGF Sud 026

  04 34 35 92 06

 

Franck Vandermoere
CRCN, CNRS


  IGF Sud 221

  04 34 35 92 13

 


Major publications

  • Cassier E, Gallay N, Bourquard T, Claeysen S, Bockaert J, Crépieux P, Poupon A, Reiter E, Marin P*, Vandermoere F*. Phosphorylation of β-arrestin2 at Thr(383)by MEK underlies β-arrestin-dependent activation of Erk1/2 by GPCRs. Elife. 2017 Feb 7;6.
  • Deraredj Nadim W, Chaumont-Dubel S, Madouri F, Cobret L, De Tauzia ML, Zajdel P, Bénédetti H, Marin P, Morisset-Lopez S. Physical interaction between neurofibromin and serotonin 5-HT6 receptor promotes receptor constitutive activity. Proc Natl Acad Sci U S A. 2016 Oct 25;113(43):12310-12315.
  • Barre A, Berthoux C, De Bundel D, Valjent E, Bockaert J, Marin P, Bécamel C. Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning. Proc Natl Acad Sci U S A. 2016 Mar 8;113(10):E1382-91.
  • Duhr F, Déléris P, Raynaud F, Séveno M, Morisset-Lopez S, Mannoury la Cour C, Millan MJ, Bockaert J, Marin P*, Chaumont-Dubel S*. Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth. Nat Chem Biol. 2014 Jul;10(7):590-7. News & Views: Seo J, Tsai LH. Neuronal differentiation: 5-HT6R can do it alone. Nat Chem Biol. 2014 Jul;10(7):488-9.
  • Lecoutey C, Hedou D, Freret T, Giannoni P, Gaven F, Since M, Bouet V, Ballandonne C, Corvaisier S, Malzert Fréon A, Mignani S, Cresteil T, Boulouard M, Claeysen S, Rochais C, Dallemagne P. Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment. Proc Natl Acad Sci U S A. 2014 Sep9;111(36):E3825-30.

 

 

Events

April 2018
Mon Tue Wed Thu Fri Sat Sun
01
02
03
04
05
07
08
09
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30