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ANR funded project

Sciences de la vie, de la santé et des écosystèmes : Physiologie, métabolisme, physiopathologie, santé publique (Blanc SVSE 1) 2010
Projet NEUROSPLICEDETAU

Implication and rescue of Tau mis-splicing in myotonique dystrophy

Myotonic dystrophy type I (DM1) is a rare inherited neuromuscular disease affecting multiple organs. The genetic mutation is located on chromosome 19 and consists of dynamic expansion of a trinucleotide motif (CTG) in the 3’ untranslated region of DM protein kinase gene (DMPK). The aetiology of DM1 relies essentially on a toxic gain of function of RNAs transcribe from the mutated gene. Thus, RNAs bearing the long CUG expansion are retained in cell nuclei, associate to RNA-binding proteins, form proteoribonuclear inclusions named foci, ultimately leading to a defective splicing of several target transcripts. The defective splicing of each transcripts can be related to a specific symptom. Central nervous system involvement in DM1 was reported long ago, but systematic studies to analyze implicated brain structures, neuropathological hallmarks and molecular mechanisms, have only been initiated. We showed an altered splicing of RNA transcripts coding for a neuronal protein essential for maintaining the architecture and plasticity of neurons, the microtubule-associated Tau. This mis splicing is associated with the development of neurofibrillary degeneration. Neurofibrillary degeneration (NFD) is a neuropathological hallmark common to more than twenty neurological disorders named Tauopathies, to which DM1 belongs. Altogether, a growing body of evidences including our data suppose that a modified splicing of Tau is likely instrumental to NFD, and myotonic dystrophy is a good model to consolidate the proof of concept of the relationship between the indirect mis splicing of Tau, brain function and the development of NFD. Therefore, our global objective is to determine the contribution of a modified splicing of Tau to the development of NFD, to reverse the mis splicing of Tau and we intend to model, study and reverse this pathophysiological mechanism in novel transgenic mouse models of NFD in DM1. To that purpose, we propose to cross DM1 transgenic mice expressing the mutated DM1 human locus with mice transgenic for the human TAU gene but invalidated for the endogenous murine Tau gene. The resulting transgenic offspring will enable to address our hypothesis. Our preliminary results demonstrated an altered splicing of Tau, hyperphosphorylation of endogenous Tau and altered synaptic plasticity in the DM1 transgenic mouse model. However, the endogenous splicing of the murine Tau is different from that of the human TAU splicing pattern. In contrast, the human TAU transgenic model is expressing the six Tau isoforms alike in the human brain. By multidisciplinary approaches and complementary expertises of the two laboratories implicated in this project, we expect to develop and characterize DM1 x human TAU transgenic mouse model that will reproduce a NFD process similar to the human pathophysiology, associated with Tau splicing defects. Moreover, our preliminary results have established that Tau mis splicing directly result from the loss of function of a splicing factor that is MBNL. We have engineered a chimeric splicing factor that enables to correct the mis splicing of Tau in vitro. Moreover, in control condition, ectopic expression of this construct is not toxic and does not regulate the splicing of Tau and other targets. We are currently producing the lentiviral vector in order to infect DM1 mice as well as the future hTAU x DM1 transgenic models. Therefore, besides being essential to address fundamental questions, the DM1 model of NFD we will develop will be very useful to test drugs and to test viral gene transfer in order to rescue in vivo the mis splicing of tau and most likely the NFD and associated symptoms. Altogether, our project aim to develop a completely novel transgenic mouse model of NFD and to rescue the pathophysiology of DM1 using a viral gene transfer therapy.

Partners

Inserm INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION DE LILLE

Inserm UNIVERSITE DE PARIS V - RENE DESCARTES

ANR grant: 514 733 euros
Beginning and duration: - 48 mois

 

ANR Programme: Sciences de la vie, de la santé et des écosystèmes : Physiologie, métabolisme, physiopathologie, santé publique (Blanc SVSE 1) 2010

Project ID: ANR-10-BLAN-1114

Project coordinator:
Monsieur Nicolas SERGEANT (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION DE LILLE)
nicolas.sergeant@nullinserm.fr

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.