Team 1 – Research interests

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hippocampe Alzheimer dégénérescences neurofibrillaires

Marquage anti-pTau de la dégénérescence neurofibrillaire dans l’hippocampe chez un patient présentant une maladie d’Alzheimer.

Équipe Alzheimer et Tauopathies
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ALZHEIMER & TAUOPATHIES TEAM

Research interests

Our project has the following scheme:

A. MAPT regulation: epigenomics, transcriptional and post-transcriptional

B. New insights on Tau functions

C. Modulating Tau pathology

D. Translational research: diagnostic and therapeutic applications

A. MAPT regulation: epigenomics, transcriptional and post-transcriptional

The human Tau / MAPT gene is unique and contains 16 exons located on more than 150 kb on the long arm of chromosome 17 (17q21). The Tau primary transcript contains 16 exons. In the human brain, exon -1 is transcribed but not translated. Exons 1, 4, 5, 7, 9, 11, 12, 13 and 14 are constituent exons. Exons 2, 3 and 10 are spliced ​​alternately and are specific to the adult brain. Thus, in the human brain, the alternative splicing of these three exons makes it possible to obtain six mRNAs (2-3-10-, 2 + 3-10-, 2 + 3 + 10-, 2-3-10 +; 2 + 3- 10+, 2 + 3 + 10 +) leading to the expression of 6 protein isoforms (3R (10-) and 4R (10+)). A growing body of literature suggests that change in alternative expression or splicing may contribute to Tau-related neurodegeneration. Thus, modification of the expression and / or splicing of MAPT leads to frontotemporal dementia but can also be observed in other Tauopathies including Alzheimer’s disease and myotonic dystrophy, CUG triplet expansion disease. It is therefore essential to understand the epigenomic, the transcriptional and post-transcriptional regulation of the MAPT gene.

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B. New insights on Tau functions

Tau protein is originally defined as a microtubule-associated protein. Tau is also a signaling protein that clearly has other functions in the neuron and neuronal networks via membrane, nuclear and extracellular processes. These new functions can be carried by specific protein domains and / or post-translational modifications (phosphorylation, acetylation, proteolysis, etc.).

In this context, the laboratory is interested in (1) the role of Tau in the nucleus in particular in the protection of nucleic acids, the structure of chromatin and transcription; (2) the role of new amino-truncated forms of Tau in neuronal signaling and physiopathological development, particularly in patients; (3) the role of Tau as an extracellular signaling factor with the aim of understanding the mechanisms leading to its secretion under physiological and pathological conditions; (4) the role of Tau as a regulator of neuronal signaling.

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C. Modulating Tau pathology

The laboratory is interested in the pathogenic role of the different molecular species of Tau especially in the prion-like spreading hypothesis. We are also interested in the role of extrinsic factors in the toxicity of these species with an interest for APP and the Tau-Aß interface, the role of potential pathological modulators resulting from proteomic / transcriptomic / genomic analyzes (GWAS with LabEx DISTALZ ), environmental factors (including caffeine and its targets, A2A adenosinergic receptors) and cellular factors (neurons vs. glial cells).

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D. Translational research: diagnostic and therapeutic applications

Our laboratory is committed to developing translational research in interface with biologists and clinicians. On one hand, we are interested in the identification of markers in autopsy-derived brain specimens and also body fluids (cerebrospinal fluid, blood…), allowing the differential diagnosis of dementia. We are developing a small cohort ECTAUSOME for a proof of concept. The emergence of new predictive biomarkers is essential for therapeutic implementation. On the other hand, we are developing preclinical research aimed at defining new therapeutic strategies. As such, we are exploring new anti-Tau compounds either by small molecule approaches (anti-aggregating, targeting protein chaperones…) in collaboration with the team of Patricia Melnyk – or immunotherapeutic approaches. The adenosinergic receptor pathway is also explored. These approaches are conducted in partnership with industry. It is notable that one of our molecules (MSBD) has led to the development of a company (AlzProtect) and a clinical trial. This molecule should move into phase 2 soon.

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In conclusion, the strength of our laboratory welcoming researchers (biochemists, cell and molecular biologists, neurobiologists) and clinicians is to integrate fundamental, pre-clinical and clinical approaches to better understand the biology of Tau, its physiopathological role and the impact in terms of diagnosis and therapy.