Summary
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the main monogenetic cause of autism spectrum disorder. FXS is caused by the epigenetic inactivation of the FMR1 gene during the first trimester of gestation. FMR1 encodes for the fragile X mental retardation protein (FMRP), which regulates the transport and translation of mRNAs involved in brain development. Already at 6 months of age, FXS infants display structural alterations in several brain areas, including the fronto-striatal circuit, suggesting an altered neural network assembly during fetal brain development. Structural anomalies in the fronto-striatal circuit may underlie symptoms that strongly impair the life of FXS patients, such as attention deficit, hyperactivity, stereotypic language and motor behavior, and problems with impulse control.
This project aims at understanding the causal factors of the altered assembly of the fronto-striatal circuit in FXS fetuses. To achieve this goal, we will generate human cortical and striatal brain organoids from FXS naïve induced pluripotent stem cells, and assemble these organoids into cortico-striatal assembloids. The resulting in vitro model will be used to conduct research in two directions. First, it will allow us to recapitulate cortico-striatal circuit assembly in FXS, identifying potential defects in axon growth and guidance, neuron morphology and neural connections. Second, we will investigate the molecular causes of these defects, in particular how the absence of FMRP affects the expression of proteins involved in the assembly of the FXS cortico-striatal circuit. These studies will make it possible, for the first time, to spatiotemporally follow the pathological events that cause FXS, both at the cellular and at the molecular level, and they will pave the way for the identification of new therapeutic strategies to prevent the development of the disease.
This project aims at understanding the causal factors of the altered assembly of the fronto-striatal circuit in FXS fetuses. To achieve this goal, we will generate human cortical and striatal brain organoids from FXS naïve induced pluripotent stem cells, and assemble these organoids into cortico-striatal assembloids. The resulting in vitro model will be used to conduct research in two directions. First, it will allow us to recapitulate cortico-striatal circuit assembly in FXS, identifying potential defects in axon growth and guidance, neuron morphology and neural connections. Second, we will investigate the molecular causes of these defects, in particular how the absence of FMRP affects the expression of proteins involved in the assembly of the FXS cortico-striatal circuit. These studies will make it possible, for the first time, to spatiotemporally follow the pathological events that cause FXS, both at the cellular and at the molecular level, and they will pave the way for the identification of new therapeutic strategies to prevent the development of the disease.
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| Web resources: | https://cordis.europa.eu/project/id/101151871 |
| Start date: | 01-09-2025 |
| End date: | 31-08-2027 |
| Total budget - Public funding: | - 188 590,00 Euro |
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Original description
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the main monogenetic cause of autism spectrum disorder. FXS is caused by the epigenetic inactivation of the FMR1 gene during the first trimester of gestation. FMR1 encodes for the fragile X mental retardation protein (FMRP), which regulates the transport and translation of mRNAs involved in brain development. Already at 6 months of age, FXS infants display structural alterations in several brain areas, including the fronto-striatal circuit, suggesting an altered neural network assembly during fetal brain development. Structural anomalies in the fronto-striatal circuit may underlie symptoms that strongly impair the life of FXS patients, such as attention deficit, hyperactivity, stereotypic language and motor behavior, and problems with impulse control.This project aims at understanding the causal factors of the altered assembly of the fronto-striatal circuit in FXS fetuses. To achieve this goal, we will generate human cortical and striatal brain organoids from FXS naïve induced pluripotent stem cells, and assemble these organoids into cortico-striatal assembloids. The resulting in vitro model will be used to conduct research in two directions. First, it will allow us to recapitulate cortico-striatal circuit assembly in FXS, identifying potential defects in axon growth and guidance, neuron morphology and neural connections. Second, we will investigate the molecular causes of these defects, in particular how the absence of FMRP affects the expression of proteins involved in the assembly of the FXS cortico-striatal circuit. These studies will make it possible, for the first time, to spatiotemporally follow the pathological events that cause FXS, both at the cellular and at the molecular level, and they will pave the way for the identification of new therapeutic strategies to prevent the development of the disease.
Status
SIGNEDCall topic
HORIZON-MSCA-2023-PF-01-01Update Date
05-10-2024
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