A word from the director
Welcome to the DHNS website. The 4 teams of our laboratory « Diseases and Hormones of the Nervous System » are working together to address unmet medical needs related to diseases and lesions of the central and peripheral nervous systems: protecting neural cells, promoting regeneration, including the regeneration of myelin, and improving functional recovery.
Research tools and strategies include translational animal disease and injury models, cultures of neural cells, organotypic cultures, the study of cellular signaling mechanisms, the regulation of disease gene expression by small interfering RNA (siRNA), the use of small neuroactive molecules as well as exploratory investigations at the cellular, genetic and epigenetic levels. Expansion of the genetic code by the incorporation of unnatural amino acids offers new perspectives for exploring signal transduction pathways.
Our research projects benefit from zebrafish, mouse, rat and also non-human primate models, the latter thanks to our collaboration with the Molecular Imaging Research Center (MIRCen). Genetic tools (conditional transgenic mouse lines) and pharmacological tools are available. Of particular support are our two technological facilities: whole exome next generation sequencing with bioinformatic analysis and the sensitive and accurate analysis and profiling of steroids in small biological samples by gas chromatography-tandem mass spectrometry (GC-MS/MS).
Neuroprotective and neuroregenerative strategies under investigation encompass the use of small multifunctional molecules, in particular steroids and ligands of the translocator protein (TSPO). A privileged mouse model for the study of the cerebroprotective effects of these compounds is ischemic stroke induced by middle cerebral artery occlusion. Within the frame of an European grant, we also explore individual neurosteroid responses to mild traumatic brain injury. An important advance was the identification of the intracellular progesterone receptors as key signal transducers of the cerebroprotective effects of progesterone. This has opened the way for additional health benefits of synthetic progestins designed for contraceptive purposes (with the Population Council, New York).
Successful nervous system regeneration also requires functional integrity of the myelin sheaths. We study the formation of myelin during development and the remyelination of axons in the context of myelin disorders. Particular attention is paid to the roles of activated astrocytes and microglial cells in myelination. We have demonstrated that the sonic hedgehog, androgen receptor and progesterone receptor signaling pathways are important players in myelin formation. Experimental models include toxin-induced demyelination of axons followed by their remyelination and experimental autoimmune encephalomyelitis. Gene therapy by adeno-associated viral (AAV) vectors is developed for the protection of neural cells and for promoting myelin regeneration.
As part of the LabEx « NanoSaclay » and in collaboration with the « National Reference Center for Familial Amyloid Polyneuropathy and other Rare Neuropathies » and with the Institut Galien, we explore the usefulness of siRNA conjugated to nanoparticles for treating monogenic peripheral neuropathies. A major step forward has been the successful completion of a Phase III clinical trial of therapeutic siRNA packaged into lipid nanoparticles for the treatment of hereditary transthyretin amyloidosis.
Small neuroactive molecules conjugated to nanoparticles also provide a unique therapeutic opportunity for accelerating and improving regeneration in the peripheral nervous system. We combine innovative microsurgical procedures with pharmacological treatments or gene therapy for improving the speed and quality of peripheral nerve regeneration. The translation of regenerative therapies from rodent models to patients is ensured by our collaboration with the Beijing Tiantan Hospital.
The development of innovative therapeutic strategies requires the identification of new targets together with functional explorations and the study of cellular signaling mechanisms. The recruitment of patients from Reference Centers of our University Hospitals has allowed us to identify new functions of genes in the development of fetal neuromuscular disorders, peripheral neuropathies and congenital anomalies of the cerebral vasculature. A first approach involves next generation sequencing of whole exomes for the identification of genes in monogenic diseases. This gene discovery effort is supported by an in-house genomic platform and bioinformatic analysis. Functional genomics are analyzed using zebrafish or mice. New insight into molecular aspects of peripheral nerve development and Schwann cell-axon interactions are obtained by in vivo manipulations and imaging in zebrafish.
In collaboration with the « Institut Baulieu », we study the role of the molecular chaperone and immunophilin heat shock protein-52 (FKBP52) in functions and dysfunctions of the microtubule-associated protein Tau. Our results point to a key role of FKBP52 in neurodegenerative diseases, in particular in tauopathies.