RNA metabolism and neurodevelopmental diseases

About

The absence of FMRP (Fragile X Mental Retardation Protein) expression in patients with Fragile X syndrome (FXS) is due to the hypermethylated expansion of a CGG repeat located in the 5′ UTR of the gene FMR1, blocking its transcription. The number of CGG repeats is polymorphic in the normal population (between 6 and 50 repeats) and increases to 55–200 in individuals carrying the premutation. The premutation is not stable during oogenesis, resulting in the production and transmission of the full mutation with a major repeat count of 200 in patients with FXS, which represents the most common form of hereditary intellectual disability. Fragile X Mental Retardation Protein (FMRP)—the product of the FMR1 gene—is an RNA-binding protein primarily involved in the control of translation and RNA transport (export from the nucleus and along dendrites) in neurons. These functions may explain the altered synaptic plasticity and morphological abnormalities of dendritic spines observed in FXS patients, as well as in the animal model of this syndrome. We use different approaches to better define the function of FMRP at the molecular level and to identify the signaling pathways that are altered in adult FXS neurons or during development. Normalizing the molecular pathology could provide clues for defining pharmacological therapy. The main research areas are:

1. Large-scale search for FMRP partners (RNA and proteins) and in particular the FMRP-RhoGTPases pathway
 
2. Role of FMRP in the early stages of neurogenesis

Different collaborations: Eric Ennifar (IBMC – Strasbourg); Hervé Moine (IGBMC – illkirch); Chrisin Gaspin (INRIA – Toulouse); Isabelle Caillé (IBPS – Paris); Patrizia D’Adamo (dibit – Milan); Lucia Ciranna (University of Catania – Catania); Viviana Trezza (Università Roma 3 – Rome); Olivier Manzoni (INMED – Marseille); Pascal Villa – (PCBi – Illkirch-France).

While FMR1 is not expressed in FXS patients, its expression is elevated (2-8 times) in patients with FXTAS (Fragile X-associated Tremor-Ataxia Syndrome), a neurodegenerative disorder affecting carriers of the FXS premutation. FXTAS patients develop a form of ataxia, parkinsonism, peripheral neuropathy, essential tremor, and memory impairment. FXTAS patients also represent a population at risk for several psychiatric illnesses. A mouse model of FXTAS exists that recapitulates this disorder. The pathophysiology of FXTAS remains largely unknown. Nuclear inclusions have been observed throughout the brains of patients as well as in the animal model. These structures were thought to cause neurodegeneration by sequestering proteins that are important for neuronal function and survival. However, more recent findings demonstrate that abnormalities in neuronal morphology and behavior in the animal model are also present prior to the generation of these inclusions. These data suggest that inclusions could represent a mechanism to protect neurons against other toxic events, such as the very high level of mRNA of Fmr1 containing augmented repeats of CGG or stress proteins.

We are investigating the role of elevated FMR1 mRNA levels on various FXTAS phenotypes (behavioral, molecular, and cellular) in mice, a model of this disorder. We are developing this project in collaboration with Drs. Mara Dierssen (CRG – Barcelona) and Rob Willemsen (Erasmus University – Rotterdam).

In collaboration with the Child Psychiatry Department of Lenval Hospital in Nice, led by Prof. Florence Askenazy, we are defining the genetic basis of the phenotype of a cohort of patients with autism and early-onset schizophrenia.