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Projects. Life and Matter Sciences

The function of the E3 ubiquitin ligase APC/C-Cdh1 in Fragile X Syndrome. Possible therapeutic application

Lead Researcher: Ángeles Almeida Parra
Research Centre: Instituto de Investigación Biomédica de Salamanca (IBSAL)


Ángeles Almeida ParraFragile X syndrome (FXS) is the most common genetic cause of hereditary intellectual disability and autism spectrum disorders, with a prevalence of 1 in 5,000 people.

Its name is due to a narrowing of the distal end of the X chromosome (Xq27.3) denominated "fragile site". FXS mainly affects males, who present a more severe phenotype than females due to the X-linked nature. FXS is caused by a trinucleotide repeat CGG expansion mutation in the promoter of the FMR1 (fragile X mental retardation 1) gene, leading to the absence (more severe cases) or reduced expression of the gene product FMRP (fragile X mental retardation protein). This protein is especially abundant in neurons and is essential to synaptogenesis and maintenance of neural circuits. However, molecular mechanisms that regulate neuronal levels of FMRP are still unknown. Recently, we have demonstrated that the E3 ubiquitin ligase APC/C-Cdh1 (Anaphase promoting complex/cyclosome-Cdh1) plays a key role in neurogenesis and synaptogenesis during development. FMRP contains consensus degradation sequences (D-box and KEN-box) recognized by Cdh1, which makes it a potential candidate to be regulated by APC/C-Cdh1. We aim to study the role of APC/C-Cdh1 in the regulation of FMRP levels in the developing brain and its implication in the dendritic and synaptic alterations associated with FXS. Within the next years we will intend to establish the relevance of Cdh1 in the FXS, which could be potentially useful to identify novel targeted molecules to develop new therapeutic strategies for this disease.

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