UMR1078

UMR 1078
Génétique, génomique fonctionnelle
et biotechnologies

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Développements biotechnologiques et approches de chémobiologie intégrée - Axe dirigé par Marc Blondel


PRiME Group

Proteinopathies and intellectual deficiency molecular mechanisms

PRiME group led by: Cécile Voisset and Gaëlle Friocourt

 

CONTACT :


 

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INTRODUCTION

I. Protein Misfolding Diseases

II. Neurodevelopmental disorders of genetic origin

Publications

Patents

Job offers

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PRiME Group Members

  • Aline BAMIA, aline.bamia(a)univ-brest.fr, +33 (0)2 98 01 83 85
  • Loubna CHAÏR, loubna.chair(a)gmail.com, +33 (0)2 98 01 83 50 / 83 85
  • Vianney DEMEOCQ, vianney.demeocq(a)gmail.com, +33 (0)2 98 01 83 85 / 80 38
  • Marc KERUZORE, marc.keruzore(a)univ-brest.fr, +33 (0)2 98 01 72 88 / 83 85
  • Adeel NASIR, anasir.adeel(a)gmail.com, +33 (0)2 98 01 73 95 / 83 50
  • Hélène SIMON, helene.simon(a)univ-brest.fr, +33 (0)2 98 01 72 88 / 83 85
  • Maha SINANE, mahasinane3(a)hotmail.com, +33 (0)2 98 01 83 87 / 80 38

INTRODUCTION

Our group is interested in pathologies affecting the brain. Our research projects focuses on two main topics:

Our aims are to get a better understanding of the molecular mechanisms involved in the above-mentioned diseases and identify drug candidates when possible.
Our group compiles various expertise, ranging from the characterization of the impact of gene mutations on mouse and human neurodevelopment to the creation of cellular (yeast or mammalian) models to study some aspects of our pathologies of interest, which can be further used to perform pharmacological screening. Affinity chromatography on immobilized drugs allows us to identify the cellular targets of these compounds. Promising drug candidates are then systematically translated in more complex systems such as organ-specific cell lines, primary neuronal cultures, organotypic brain slice cultures or directly in mouse models.

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I. Protein Misfolding Diseases

Our group mainly focuses on neurodegenerative proteinopathies like prion diseases, Parkinson’s, Alzheimer’s and Huntington’s diseases. We are nonetheless also interested in pathologies involving amyloid formation that do not affect the brain.

Neurodegenerative proteinopathies

Although the concept of infectious proteins was first established for the prion protein PrP in mammals suffering from transmissible spongiform encephalopathy, prions are broadly found in other model organisms such as the budding yeast S. cerevisiae. In the last years, we have identified new anti-prion compounds by screening for drugs able to cure [PSI+] and [URE3] yeast prions. Some of the compounds we identified turned out to be also active in vitro and in vivo against mammalian prions PrPSc, allowing us to demonstrate that some molecular mechanisms controlling prion onset and propagation are conserved from yeast to human.
There is now a growing number of evidence that neurodegenerative protein misfolding diseases like Alzheimer’s, Parkinson’s and Huntington’s diseases share key biophysical and biochemical characteristics with prionopathies. However, the molecular mechanisms of propagation of the pathological conformation of the proteins associated to these pathologies are still unknown.
In this context, the aim of our projects is to characterize new therapeutic pathways to curb the spread of the pathological conformation of proteins associated with human proteinopathies.
Among the drugs we identified, 6-aminophenanthridine (6AP) and two FDA-approved drugs, guanabenz (GA) and imiquimod (IQ), specifically interact with the domain V of the large rRNA of the large subunit of the ribosome, a ribozyme with two enzymatic activities: (i) the peptidyl transferase activity, and (ii) a poorly characterized protein folding activity, PFAR, which is able to refold denatured proteins to their functionally active form. We showed that 6AP, GA and IQ are competitive inhibitors of PFAR, the first ones described so far, which led us to explore the link between PFAR and the propagation of the yeast prion [PSI+] and to recently demonstrate that PFAR is linked to the propagation of [PSI+] prion in yeast.
We are currently studying the potential of PFAR as a therapeutic target for treating human protein folding disorders. We also seek to decipher the molecular mechanisms of pathological conformation propagation of proteins associated with human proteinopathies in order to identify new therapeutic avenues.

Other proteinopathies

p53 dominant-negative mutants - p53 is a tumor suppressor gene essential for protection against cancer. It encodes the p53 transcription factor that regulates a very large number of target and miRNA genes involved in cell cycle, metabolism or even apoptosis. In case of damage to DNA (U.V.) or stress, p53 induces cell cycle arrest and DNA repair. When this repair fails, p53 triggers apoptosis of the cell, preventing the spread of damaged cells. The p53 gene is found to be mutated in up to 50% of human cancers. While most of the mutations affecting tumor suppressor genes are recessive, p53 shows many dominant-negative mutations. They produce mutant proteins capable, for some of them, to form amyloid fibers. These amyloid fibers sequester the functional wild-type form of p53 in the cell. Tumors with dominant-negative p53 mutations are associated with a poor prognosis for the patient as well as increased resistance to chemotherapy. We have recently shown that the behavior of dominant-negative p53 mutants is not based on a prion-like mechanism.

Collaborations

  • F. Bihel (CNRS UMR7200, Strasbourg, France)
  • V. Béringue and M. Moudjou (INRA, Jouy-en-Josas, France)
  • S. Sanyal (BMC, Uppsala, Sweden)
  • H. Galons (Inserm U648, Université Paris V, France)
  • S. Saupe (IBGC, Bordeaux, France)
  • M. Simonelig (IGH, Montpellier, France)
  • C. Trollet (Pitié Salpétrière, Paris, France)
  • M. Lecourtois (Inserm U1079, Rouen, France)
  • S. Chédin and JY. Thuret (CEA, Saclay, France)
  • G. Stahl (LMGM, Toulouse, France)
  • C. Hetz (Santiago University, Chile)
  • R. Gillet (CNRS, Rennes, France)
  • R. Bujdoso and A. Thackray (Cambridge University, UK)
  • P. Sibille (INRA, Jouy-en-Josas, France)
     

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II. Neurodevelopmental disorders of genetic origin

We focus our research on two groups of diseases, ARX-related forms of intellectual disability and Down syndrome, resulting from the presence of 3 copies of chromosome 21.

ARX related forms of intellectual disability

The gene encoding the transcription factor ARX (aristaless-related homeobox gene) has been shown to be responsible for a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to milder forms of X-linked intellectual deficiency often associated with epilepsy but without apparent brain abnormalities. In the last years, we have first investigated the role of the most severe mutations of ARX which result in a rare form of lissencephaly (the XLAG) characterised by an almost complete absence of GABAergic neurons in the cortex of patients. We also sought to identify the molecular pathways and the genes regulated by ARX. More recently, we have investigated the impact of less severe mutations, such as the most frequent mutation identified in ARX, a duplication of 24 pb in a polyalanine stretch. Using a mouse model for this mutation, we have shown that this mutation leads to mild defects in the development of GABAergic neurons, resulting in a very similar phenotype in mouse and human patients characterized by mild cognitive defects, infantile spasms in 10% of the cases and defects in fine motor abilities. We are now using this mouse model to better understand the role of ARX and GABAergic neurons in the development of reaching/grasping abilities and the impact of ARXdup24 mutation in the development of the cerebral structures involved in these processes.

Down syndrome

Concerning Down syndrome, we focus on the study of the impact of CBS (Cystathionine beta synthase) triplication on cell function. Recent studies from our collaborators have shown that cbs triplication is necessary and sufficient to induce cognitive defects in mouse, suggesting that this gene may play an important role in the cognitive phenotype of patients with Down syndrome. CBS catalyzes the condensation of homocysteine and serine to form cystathionine. This reaction represents the first committed step in the transsulfuration pathway for cysteine and glutathione (GSH) synthesis. This pathway plays important roles in clearing homocysteine, in methionine homeostasis, and in providing cysteine especially in cells that exhibit a high turnover of the major cellular antioxidant, glutathione. Loss of function mutations of CBS are associated with homocystinuria, a metabolic condition characterized by the presence of homocysteine in patients’ urine and featuring intellectual disability. We have recently identified drug candidates which compensates for cellular dysfunction due to CBS overexpression in yeast. One of this drug restores normal cognitive abilities in cbs-triplicated mice. We are now investigating their mode of action and testing whether these molecules are also efficient in cellular models for Down syndrome (fibroblasts and iPS). 

Collaborations

  • A. Dubos, V. Brault and Y. Hérault, CNRS UMR7104, INSERM U964, ICS and IGBMC, Strasbourg
  • F. Bihel, UMR7200 CNRS, Strasbourg
  • A. Curie and V. des Portes, L2C2, CNRS UMR5304, Lyon
  • P. Marcorelles, CHRU Brest
  • A. Laquerrière, CHU Rouen
  • C. Shoubridge, Adelaide University, Australia
  • E. Bellefroid, University of Brussels
  • J. Chelly, CNRS UMR7104, INSERM U964, IGBMC, Strasbourg

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