CLARKE  GROUP

Group leader

Prof. Peter G.H. Clarke

Group members

Anne-Caroline Bessero, doctoral student
Vanessa Ginet, doctoral student (in collaboration with the group of Dr. Anita Truttmann)
Vincent Mottier, technician
Guylène Magnin, technician (in collaboration with the group of Dr. Anita Truttmann)
Sonia Naegele-Tollardo, technician
Dr. Julien Puyal, post-doc
Anne Vaslin, doctoral student

Neuronal death

Our longstanding research theme is neuronal death. Even in normal development, many neurons die, and understanding the developmental role and trophic control mechanisms of this death this was the focus of our previous research (until about 1998).

Current research focus: excitotoxicity

For the last six years we have been focusing on excitotoxicity, which means the toxic effect of excessive activation. It is the main cell death mechanism in many clinical conditions including cerebral ischemia, traumatic brain injury, perinatal asphyxia and epilepsy, and it contributes to neuronal death in glaucoma.

1. Neuroprotection by inhibiting the JNK pathway (in collaboration with Dr. C. Bonny, Lausanne, Dr. Tiziana Borsello, Lausanne and Milan, Dr. L. Hirt, Lausanne,. Dr. Anita Truttmann, Lausanne and Prof. A. Vercelli, Turin

We have evidence - in vitro and in vivo - that exceptionally strong protection can be obtained against excitotoxicity and ischemic neuronal death by inhibition of the JNK pathway using peptide inhibitors developed by Dr. Christophe Bonny and his group. The neuroprotection is accompanied by behavioural sparing. We are currently analysing the cellular mechanisms and evaluating the clinical potential, particularly in relation to cerebral ischemia, perinatal hypoxia and glaucoma.

2. Endocytosis and autophagy in excitotoxically stressed neurons

We have evidence that endocytosis and autophagy are involved in certain kinds of cell death, and have recently showed that this is true of excitotoxicity. We are currently studying the significance of these events in the cell death process and are investigating whether the endocytosis can provide a means to target inhibitors specifically into excitotoxically stressed neurons.

STRESSPROTECT

STRESSPROTECT is an EU-financed project carried out by 8 European research groups, including our own, on the theme: "Targeting of stress kinase signalling as therapeutic strategy against excitotoxicity". Stress kinases are MAPkinases of the JNK and p38 families.

The ultimate aim of the project is to develop new drugs, especially peptidic drugs, as exemplified by XG-102 (D-JNKI1) - see our 2003 paper in Nature Medicine (pdf). XG-102 will soon be brought to clinical trials by the Lausanne biopharmaceutical company Xigen. However, this long term therapeutic aim will require a much deeper understanding of the role of the stress kinase pathways in excitotoxicity, and most of STRESSPROTECT is devoted to fundamental research on the stress kinase pathways.

The main role of our group in STRESSPROTECT stems from our discovery of strongly activated endocytosis in excitotoxicity, including cerebral ischemia. We are attempting to understand three aspects of this endocytosis:
1) What are the pathways that activate it? We already know that the JNK pathway is involved.
2) Does it play a role in mediating excitotoxic neuronal death?
3) Can it be used for targeting drugs preferentially into stressed cells?

Recent publications

2006

C. Centeno, M. Repici, J.-Y. Chatton, B. M. Riederer, C. Bonny, P. Nicod, M. Price, P.G.H. Clarke, S. Papa, G. Franzoso & T. Borsello (2006) Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons. Cell Death Differ.

A. Guillon-Munos, M.X.P. van Bemmelen & P.G.H. Clarke (2006) Autophagy can be a killer even in apoptosis-competent cells. Autophagy 2, 140-142.

2005

R. Kohli, J.-P. Gabriel & P.G.H. Clarke (2004) Mathematical analysis of competition between sensory ganglion cells for neurotrophic factor in the skin. Math. Biosci. 191, 207-225

2003

T. Borsello, P.G.H. Clarke, L. Hirt, A. Vercelli, M. Repici, D.F. Schorderet, J. Bogousslavsky & C. Bonny (2003) A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity. Nature Medicine 9, 1180-1186. [Pdf]

T. Borsello, K. Croquelois, J.P. Hornung and P.G.H. Clarke (2003) NMDA-triggered neuronal death in organotypic hippocampal cultures is endocytic, autophagic and mediated by the JNK pathway. Eur. J. Neurosci. 18, 473-485

T. Borsello, R. Bressoud, V. Mottier, N. González, G.l Gomez and P.G.H. Clarke (2003) Kainate-induced endocytosis in retinal amacrine cells. J. Comp. Neurol. 465, 286-295.

S. Przedborski & P.G.H. Clarke (2003) Cell death pathways in amyotrophic lateral sclerosis. In: "Motor Neuron Disorders", Ed.: P. J. Shaw and M.J. Strong. Butterworth & Heinemann, pp 357-377.

P.G.H. Clarke (2003) Models of neuronal death in vertebrate development: from trophic interactions to network roles. In: "Modeling Neural Development", Ed. Arjen van Ooyen. MIT Press, Cambridge, Mass., pp 167-182.

2002

Tiziana Borsello, Vincent Mottier, Vincent Castagné & Peter G.H. Clarke (2002) Ultrastructure of retinal ganglion cell death following axotomy in chick embryos. J. Comp. Neurol. 453, 361-371

 K. Lefèvre, P.G.H. Clarke & V. Castagné (2002) Involvement of cyclin-dependent kinases in axotomy-induced retinal ganglion cell death. J. Comp. Neurol. 447, 72-81..

P.G.H. Clarke (2002) From morphological types of cell death to interacting pathways. Trends Pharmacol. Sci. 23, 308-309.
 

2001

Castagné, K. Lefèvre & P.G.H. Clarke (2001) Dual role of the NF-KB transcription factor in the death of immature neurons. Neuroscience 108, 517-526.

2000

Cuadros, M.A.,  D. Martin, D. Pérez-Mendoza, J. Navascués & P.G.H. Clarke (2000) Response of macrophage/microglial cells to experimental neuronal degeneration in the avian isthmo-optic nucleus during development. J. Comp. Neurol. 423, 659-669.

Castagné, V., & P.G.H. Clarke (2000) Neuroprotective effects of a new glutathione peroxidase mimetic on neurons of the chick embryo's retina. J. Neuroscience Res. 59, 497-503.

1999
 

Castagné, V., M. Gautschi, K. Lefèvre, A. Posada & P.G.H. Clarke (1999) Relationships between neuronal death and the cellular redox status. Focus on the developing nervous system. Progress in Neurobiology 59, 397-423.

Castagné, V.,  &  P.G.H. Clarke (1999) Inhibitors of mitogen-activated protein kinases protect axotomized developing neurons. Brain Res. 842, 215-219.

Posada, A., &  P.G.H. Clarke (1999) The role of neuronal death during the development of topographically ordered projections: a computational approach. Biol. Cybernetics 81, 239-247.

Castagné, V.,  P. Barneoud & P.G.H. Clarke (1999) Protection of axotomized ganglion cells by salicylic acid. Brain Res. 840, 162-166.

Castagné, V.,  K. Lefèvre, R. Natero, D.A. Becker & P.G.H. Clarke (1999) An optimal redox status for the survival of axotomized ganglion cells in the developing retina. Neuroscience 93, 313-320.

Posada, A. &  P.G.H. Clarke (1999) Role of nitric oxide in a fast retrograde signal during development. Dev.Brain Res. 114, 37-42. Abstract.

Posada, A. & P.G.H. Clarke (1999) Fast retrograde effects on neuronal death and dendritic organization: the role of calcium influx. Neuroscience 89:399-408. Abstract.

Clarke, P.G.H. (1999) Apoptosis versus necrosis: How valid a dichotomy for neurons? In V. Koliatsos and R.R. Ratan (eds): Cell Death and Diseases of the Nervous System. Totowa,N.J.: Humana Press, pp. 3-28.

1998

Castagné, V. and P.G.H. Clarke (1998) Cooperation between glutathione depletion and protein synthesis inhibition against naturally occurring neuronal death. Neuroscience 86:895-902. Abstract.

Clarke P.G.H., Posada A., Primi M.-P. and Castagne V. (1998) Neuronal death in the central nervous system during development. Biomedicine & Pharmacotherapy52(9):356-362.Abstract.

1997

Primi, M.P. and P.G.H. Clarke (1997) Early retrograde effects of blocking axoplasmic transport in the axons of developing neurons. Dev.Brain Res. 99:259-262. Abstract.

Primi, M.P. and P.G.H. Clarke (1997) Presynaptic initiation by action potentials of retrograde signals in developing neurons. J.Neurosci. 17:4253-4261. Abstract.

Castagné, V. and P.G.H. Clarke (1997) Inhibition of glutathione synthesis can enhance cycloheximide-induced protection of developing neurons against axotomy. Brain Research. 102:285-290.Abstract.

Kohli, R. and P.G.H. Clarke (1997) Mathematical analysis of competition between sensory ganglion cells for nerve growth factor in the skin. Lect.Notes Comput.Sci. 1327:133-138.

1996

Castagné, V. and P.G.H. Clarke (1996) Axotomy-induced retinal ganglion cell death in development: Its timecourse and its diminution by antioxidants. Proc.R.Soc.Lond.[Biol.] 263:1193-1197. Abstract.

Clarke, P.G.H. and S. Clarke (1996) Nineteenth century research on naturally occurring cell death and related phenomena. Anat. Embryol.(Berl) 193:81-99. Abstract.

Clarke, P.G.H., M. Gyger, and S. Catsicas (1996) A centrifugally controlled circuit in the avian retina and its possible role in visual attention switching. Vis.Neurosci. 13:1043-1048. Abstract.

Clarke, P.G.H. and R. Kraftsik (1996) Dendritic reorientation and cytolamination during the development of the isthmo-optic nucleus in chick embryos. J.Comp.Neurol. 365:96-112. Abstract.

Jeanprêtre, N., P.G.H. Clarke, and J.P. Gabriel (1996) Competitive exclusion between axons dependent on a single trophic substance: A mathematical analysis. Math.Biosci. 135:23-54. Abstract.

Primi, M.-P. and P.G.H. Clarke (1996) Retrograde neurotrophin-mediated control of neurone survival in the developing central nervous system. Neuroreport 7:473-476. Abstract.