1983-1988: PhD student in the Laboratory of Pr. M.Schachner
Institut für Neurobiologie, Heidelberg, FRG
PhD of the University "Aix-Marseille II"
Keywords: Cell adhesion molecules, N-CAM, L1, MAG, nervous system development, Myelin
1988- 1989: Post- doc Institut für Neurobiologie, Heidelberg, FRG
1990-1991: Post-doc McGill Cancer Centre, Montréal, Canada.
Keywords: development, homeobox
1991-1997: Team leader at the Geneva Biomedical Research Institute Geneva, Switzerland.
Keywords: apoptosis, Bax, Bcl-2, neuronal death
1997-1999: Project leader, Multiple Sclerosis,
Serono Pharmaceutical Institute Geneva, Switzerland
Keywords: auto-immune, Myelin,
Since June 1999: full Professor at the University Joseph Fourier, Grenoble, France
Director of the team Neurodegeneration and Plasticity
Inserm (E108 (2001-07)
Grenoble institute of Neuroscience, Team 2, Inserm U836 (2007- )
Keywords: FTD, Alzheimer, neuronal death, death receptors, endosomes, exosomes, synaptic plasticity
57 refererenced publications,
H index 30; average citation 85,11; total of 4851 citations
(source : ISI Web of knowledge 03/2011)
Endocytosis is the major way for regulating protein expression at the cell surface. Endocytosed molecules traffic through intracellular compartments called endosomes, within which they are sorted to other organelles, the cell surface, the extracellular space or lysosomes. Several neurodegenerative diseases are linked with mutations in effectors of the endosomal pathway and severe impairments of this system were described in diseased neurons. This begs the question of the relationship between these abnormalities and two characteristics of neurodegenerative pathologies: synaptic impairments and neuronal death.
Endocytosed proteins meant for elimination are selectively entrapped into vesicles budding from the endosomal membrane into the lumen of endosomes. Such a process leads to the formation of endosome intermediates called multivesicular bodies (MVBs), filled with intralumenal vesicles. The latter and their cargoes will be hydrolysed after fusion of MVBs with lysosomes. Fusion of MVBs can also occur with the plasma membrane to allow secretion of the vesicles which, once in the extracellular milieu are referred to as exosomes. Sorting of endocytosed membrane proteins inside intralumenal vesicles of MVBs requires cytosolic proteins associating onto endosomes to build the endosomal sorting complex required for transport (ESCRT). For several years our work has focused on several molecular aspects of biogenesis and function of MVBs in neurons, specifically regarding synaptic physiology and neuronal death. The three main projects deal with: 1) CHMP2B , an ESCRT protein mutated in Fronto-Temporal Dementia (FTD). We found that the protein modulates shaping of dendritic spines of glutamatergic synapses and that FTD mutations impair this function. 2) Alix, an adaptor protein discovered in our lab, which binds ESCRT proteins and impacts on MVB biogenesis. We showed that Alix is involved in neuronal death and decrypted its mode of action: the protein regulates activation of caspases by endocytosed death receptors and calcium elevation. This is the first direct link between ESCRTs and the apoptotic machinery. 3) Neuronal exosomes. We found that CNS neurons release exosomes in a way regulated by synaptic activity suggesting a role in synaptic physiology and transynaptic passage of pathological agents within the CNS.