NORMAL AND PATHOLOGICAL NEUROBIOLOGY IN DROSOPHILA
Department: Neurosciences - Research axis: Molecular & cellular networks

Research subject

Our team develops two main axes of research: the first one consists in studying the mechanisms responsible for the normal functioning of the nervous system, especially looking at the microtubule cytoskeleton. Our research projects take advantage of the genetic potential of the model organism Drosophila melanogaster (the fruitfly) – this also allows the reduced use of Vertebrate model animals such as mice and rats. They aim at understanding how the microtubules control the shape and the physiology of the axons and the synaptic terminals. We are looking more particularly at the role of tubulin post-translational modifications, such as polyglutamylation. We also study the role of microtubule-associated proteins, such as MAP1 and tau/MAP2 proteins.

The second axis of research consists in studying the physiopathological mechanisms that occur during neurodegenerative diseases such as Huntington’s disease or tauopathies. For example, for Huntington’s disease, we have shown that the normal Huntingtin protein (the non-mutated one) played a protective role with respect to the toxic effects of the mutated Huntingtin (with a polyQ repeat) present in patients. According to this result, we have found a peptide that is able to counteract many cellular, physiological and behavioural defects induced by the mutated protein (patent filed). Our research now focuses on the cellular toxicity due to the microtubule-associated protein Tau. This protein is highly phosphorylated and is found in neurofibrillary tangles in several neurodegenerative diseases like Alzheimer’s Disease and other tauopathies (Frontotemporal dementias, Pick’s disease, corticobasal neurodegeneration, progressive supranuclear palsy ???). This work started with a grant from France Alzheimer, and could then be continued thanks to the Diatral (Diagnostic and Treatment of Alzheimer ‘s Disease) project. We could show that an excess of hypophosphorylated, microtubule- bound Tau was actually much more toxic for the neurones than an excess of hyperphosphorylated, microtubule-unbound Tau (Talmat-Amar et al, Human Molecular Genetics 2011). This leads to the conclusion that current therapeutic strategies aimed at dephosphorylating Tau to cure Alzheimer’s disease and other tauopathies may have strong side effects because of an excess of Tau bound to the microtubules. We are currently looking for new ways of controlling Tau binding to the microtubules, independently of phosphorylation, in order to imagine new innovative therapeutic strategies.
We also recently found that an excess of Tau protein impairs cell division (Bougé et al. 2016). This open new perspectives related to the understanding of Tau toxicity: not only this toxicity may occur in tissues different from the nervous system, but also this may occur in nervous system stem cell rather than in differentiated neurons only.

 

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Team

Team leader

Marie-Laure Parmentier
DR2, Inserm


  IGF Sud 116

  04 34 35 92 17

 

Staff

Sophie Layalle
CRCN, Inserm


  IGF Sud 116

  04 34 35 92 17

 

Laurent Soustelle
CRCN, Inserm


  IGF Sud 116

  04 34 35 92 17

 


Major publications

• Bougé A.L. and Parmentier M.-L. (2016) Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death. Dis Model Mech. 2016, Mar 1;9(3):307-19
• Lepicard S., Franco B., de Bock F. and Parmentier M.-L. (2014) A presynaptic role of microtubule-associated protein 1/Futsch in Drosophila: regulation of active zone number and transmitter release. J Neurosci. 34(20):6759-71
• Arribat Y., Bonneaud N., Talmat-Amar Y., Layalle S., Parmentier M.-L., Maschat F.. (2013) A huntingtin peptide inhibits polyQ-huntingtin associated defects. PLoS ONE 8(7): e68775
• Talmat-Amar Y., Arribat Y. Redt-Clouet C., Feuillette S., Bougé A.-L., Lecourtois M., Parmentier M.-L. (2011) Important neuronal toxicity of microtubule-bound Tau in vivo in Drosophila. Hum. Mol. Genet. 20(19) :3738-45.
• Mitri C., Soustelle L., Framery B., Bockaert J., Parmentier M.-L. and Grau Y. (2009) Plant insecticide L-canavanine repels Drosophila, via the insect orphan GPCR DmX. PLoS Biology 7(6): e1000147.Cited by the Faculty of 1000 (Faculty of 1000: 2009. F1000.com/1279959)

 

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