Reference:
ANR-12n.a.003-BSV1
Abstract:
The MeCP2-pathies represent a field of particularly dynamic and competitive research in the field of intellectual disabilities related to the X chromosomeﾠRett syndrome (RTT) is the prototype of these diseases and account for 10% of cases of mental retardation of genetic origin in women.ﾠThe causative gene is Mecp2 encoding a multifunctional protein that modulates gene expression by several independent mechanisms.ﾠIn addition to the RTT, we know twice as many patients (male or female) with mutations in the MECP2 gene causing neurological disorders of varying severity.Overall, mutations in MECP2 affects 30,000 new patients each year worldwide.ﾠAll these cases are sporadic and genetic counseling and prenatal diagnosis are not possible which causes their prevalence will never change.ﾠTo date there is no treatment. Recently, we made an important discovery showing that axonal transport is affected in the absence of MeCP2. The Bdnf is a target of MeCP2. We have shown that several genes involved in the trafficking of Bdnf as huntingtin (Htt) and the huntingtin-associated protein (Hap1) are deregulated in the brains of MeCP2-deficient mice. We have shown that the velocity of BDNF vesicular transport in MeCP2-deficient axons is reduced and the re-expression of these neurons in MeCP2 restores their phenotype. The purpose of this project is to study more intensively mechanisms driving the transport deficit in MeCP2-deficient neurons and to identify pharmacological agents potentially able to offset such deficits. Vesicular transport is not only dependent on the amount of molecular motors and associated proteins (dynein, dynactin, Htt, Hap1), but also requires the intervention of a number of kinases. The Akt signaling pathway has been described as one of the main regulators of Htt phosphorylation, resulting in an accelerated return axonal transport. Recently, it was shown that activation Akt was altered in the cortex of MeCP2-deficient mice. We will determine whether the main partners of the Akt pathway, particularly Htt are affected by the absence of MeCP2. We will also assess the impact of in vivo pharmacological agent (FK506) able to maintain the high level of phosphorylation of Htt in MeCP2-deficient mice our. The Akt pathway is also highly dependent on the activation of receptors Insuline/IGF1. IGF1 is dysregulated in the brains of mouse MeCP2-deficient. We will assess whether pharmacological stimulation of receptors Insuline/IGF1 can restore some deficits Akt pathway but also some functions in vivo. Our previous results showed that in addition to Htt and Hap1, other molecular motors are severely affected in MeCP2-deficient neurons. These factors are not only involved in vesicle transport Bdnf also other cargo and mitochondria. We will assess whether part of RTT phenotype is not due to an alteration of vesicular transport of mitochondria and / or energy metabolism. The MeCP2 protein is localized in the nucleus. In contrast, molecular motors are present in the cytoplasm. In our previous study we proposed that deficits in MeCP2 lead to an alteration of vesicular transport via transcriptional dysregulation. We will try to better understand the proposal and evaluate an alternative hypothesis which would play a role in MeCP2 in the cytoplasm. All these results allow a better understanding of MeCP2-pathies but also the development of new pharmacological tools to improve the lives of patients.
PROJECT DETAILS
beginning: 2012.
end: 2015.
Country of research: France
Counry of funding source: France
Funding organization: The French National Research Agency
Financing: NATIONAL FUNDINGS – 392 094 €