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Mécanismes moléculaires dans les démences neurodégénératives (MMDN)
Unité mixte INSERM, Université Montpellier 2, Ecole Pratique des Hautes Etudes
Secrétariat : Martine Destrade / Chantal Kindou
Adresse : Université Montpellier 2 - Place Eugène Bataillon - CC105 - 34095 Montpellier cedex 05
The lab « Molecular Mechanisms in Neurodegenerative Diseases » (MMDN) is an interdisciplinary lab dedicated to research on the biology of ageing and of neurodegenerative diseases, from cells to humans. The overall scientific aim of MMDN is to improve our understanding of the molecular and social bases of "normal" ageing, as well as of neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), prion and Hungtinton’s (HD) diseases, and to suggest new approaches for diagnosis, care and treatment. Our research is based on 3 specific themes :
- Processes in ageing: from single cells to humans. Ageing is a continuum process that begins at conception, continues during development and for as long as we live. The main originality of the lab is that we are able to study ageing from the level of single neurons, to the level of human populations.
- Conception and development of experimental models. Our goal is to identify and understand the early mechanisms of neurodegenerative processes before deleterious signs appear. We are developing various and complementary systems for the analysis of ageing and neurodegeneration, both in vitro (cell cultures) and in vivo (zebrafish, mice, rats, and primates).
- Therapeutic strategies. Using our various animal models, we develop specific strategies in dealing with prion diseases and with AD. Regarding prion diseases, we have used an original approach consisting in lentiviral gene transfer of dominant negative prion protein. Regarding AD, we developed anti-Ab immunotherapy and pharmacotherapy aimed at original targets involved in endogenous neuroprotection, like the s1 chaperone.
Team 1: J.M. Verdier.
Current knowledge is insufficient to identify the molecular and cellular mechanisms that underly brain ageing, and its transition into neurodegenerative diseases. In order to propose diagnostic and therapeutic approaches, understanding and differentiating physiological brain ageing vs pathological developments remains a most important scientific challenge.
The overall scientific aim of Team 1 is to improve our understanding of the molecular bases of neurodegenerative diseases, such as Alzheimer, Parkinson and prion diseases, as well as of healthy aging, in order to suggest new approaches for diagnosis and treatment. For that purpose, we designed and used animal experimental and cell models:
- Using the primate model Microcebus murinus (MIM), we are gaining insights into ageing, as well as into the natural history of AD, the transmissibility of peculiar prion strains, or the efficacy of gene transfer for therapeutic purposes in a reasonable period of time. In addition, our population is available for longitudinal studies for prediction and follow-up of treatment through read-outs that mimic those used in human populations, but in a more controlled and reproducible environment ;
- Because synaptic rearrangement plays a major role during ageing, studying ageing at the single-cell level should provide informations that are impossible to get at the global brain level. We have therefore developed an original approach in zebrafish to permanently label one or a few sensory neurons, thus allowing us to follow neural regeneration and more generally neural re-modeling throughout life, at the single-cell level.
Team 2: T. Maurice
We identify and validate new pharmacological targets in Alzheimer's disease (AD) with high neuroprotective value. Our "historical" target is the sigma-1 (σ1) protein, identified in 2007 as a ligand-operated endoplasmic reticulum (ER)-resident chaperone. The σ1 protein acts as a sensor/modulator of cellular responses (responses to ER stress and oxidative stress, ER-mitochondrial Ca2+ homeostasis, modulation of ion channel activity). Polymorphims in the σ1 protein gene have been recently described as vulnerability/protective factors in AD and activation of the protein has been shown to protect against ischemia/stroke and several degenerative pathologies including AD or amyotrophic lateral sclerosis. Our team contributes to the analysis of the σ1 protein activity in brain plasticity, to the definition of its mechanism of action and to the in vivo validation of new, selective or non-selective, σ1 agonists as neuroprotectants in AD.
Oxidative processes are particularly involved in AD etiology, and antioxidants (vitamin E) showed some efficacy in the disease treatment or prevention. We identified a new promising protective target, the plasma phospholipid transfer protein (PLTP). PLTP transports not only cholesterol but also vitamin E. It is highly expressed in the central nervous system and also present in the cerebrospinal fluid. Alterations in PLTP expression have been shown in patients with AD and other neurodegenerative disorders. We showed that PLTP deficiency is a vulnerability condition facilitating AD toxicity and we identified original pharmacological approaches to boost PLTP activity in AD models.
Activation of several kinases is involved in AD pathology and their roles at the cross-talk between the accumulation of Aβ and the hyperphosphorylation of Tau protein may be largely underestimated. We focus on the dual-specificity tyrosine phosphorylation regulated kinase 1A (Dyrk1A) that has important and harmful functions, not only in the amyloid pathology developing in Down syndrome patients but also, to an unknown extent, in AD.
These projects are developed using several AD Tg mouse lines bred in the lab, but numerous data were rapidly obtained through our expertise in a non-transgenic acute AD model, the oligomeric Aβ25-35 injection model in rodents. The model has been described decades ago, but we contributed an in-depth validation in the rat. We continue to document its validity and take advantage of its reliability to determine: (1) the impact of Aβ toxicity on the hypothalamo-pituitary adrenal (HPA) axis and its involvement in the etiology of AD, and (2) the involvement of a neuroprotective system (BDNF), and particularly the p75 receptor, in the toxicity.
Team 3: V. Perrier and M. Rossel.
The ageing process is driven by the accumulation of molecular damages causing changes in cell metabolism and tissue functions. The balance between healthy and pathological ageing relies on multiple factors. The understanding of the early stages of the rupture of this balance is a key point in the understanding of neuropathological diseases (AD, tauopathies, CJD).
Team 3 objective is to understand the early mechanisms involved in neurodegenerative diseases, and to define new diagnostic and therapeutic strategies. To fulfill this objective, we have chosen multidisciplinary approaches ranging from biophysical and cellular studies to in vivo approaches. We focus on two proteins involved in developmental processes and neurodegenerative diseases: PrP and Reg-1a (following previous AERES recommendations). Autocatalytic cleavage of Reg-1a leads to the formation of quadruple-helical fibrils. Thus Reg-1a strongly resembles both the prion protein in its dramatic proteolysis and amyloid proteins in its ability to form fibrils.
Team 4: J.M. Robine
In low mortality countries displaying the highest level of development, such as the OECD countries, life expectancy at birth has reached unexpected high levels and keeps increasing by circa 3 months per year without any sign of slowdown. Therefore these countries are quickly accumulating extremely old people such as nonagenarians, centenarians and now supercentenarians. Little is known on the health status and quality of life of these people because most studies and population surveys consider only the 85+ as the lasted age group with very few people above the age of 90 years under study for a variety of “good” reasons (i.e., place of residence, frailty, sensory and cognitive impairments). In this context theories propose several possible futures and scenarios from compression to expansion of morbidity, frailty and disability.
The main objective of Team 4 is to understand the relationship between health and longevity. For that purpose, we focused on several aspects, from conceptual and methodological aspects to the empirical ones:
- Measures and limits of the human longevity
- Measure of health and quality of life among the oldest old, combining quantitative approach through epidemiological surveys and qualitative approach through ad-hoc anthropological studies
- Combined measures of health and longevity through the development of summary measure of population health
Team 5: F. Maschat
During the construction of mature nervous systems, much of the neuronal wiring takes place during embryonic development. Transcription factors such as Engrailed homeoprotein that are highly conserved from Drosophila to humans have been found to be required for specific axon guidance events. Because of the genetic tools developed in Drosophila, this model organism is particularly powerful for such a study.
Our objective concerns the understanding of the construction of a nervous system and of its destruction in the case of neurodegenerative diseases. To this end, we have developed two axes: the first one concerns the study of the homeoprotein Engrailed during neurogenesis, whereas the other part concerns more applied research dedicated to fight neurodegenerative diseases, such as Huntington’s disease with the identification of protective factors against this disorder. We recently identified a peptide with protective properties in HeLa cells in culture, in vivo in HD Drosophila model, and on a mouse model of HD, using a new oral spray delivery, where the peptide has been inserted in a water-in-oil microemulsion (Aonys technology developed by Medesis Pharma).