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

18th national competition for scientific and technical research

Rare diseases

Senior Researcher : Ángeles Almeida Parra

Research Centre or Institution : Instituto de Investigación Biomédica de Salamanca (IBSAL). CSIC-Universidad de Salamanca.


Fragile X chromosome syndrome (FXS) is the most frequent genetic cause of hereditary intellectual disability and autism spectrum disorders. FSX is caused by mutations in the FMR1 gene, leading to loss or reduction of RNA binding protein FMRP expression, which has been related to a greater or lesser severity of intellectual disability. Previously, we have described that the E3 ubiquitin ligase APC/C-Cdh1 plays a key role in the prenatal development of the cerebral cortex. Thus, genetic loss of Cdh1 causes neural precursor death, altering the balance between proliferation and neuronal differentiation, which culminates in microcephaly. The main objective of the project is to study the role of APC/C-Cdh1 in the regulation of FMRP levels in the developing brain and its impact in the FXS pathophysiology. Here, we demonstrate that FMRP is a target of APC/C-Cdh1. During neuronal differentiation, FMRP levels decrease as a result of the increase in the ligase activity. FMRP accumulates in neurons lacking Cdh1 (KOCdh1), causing neuronal apoptosis. Similarly, FMRP accumulates in brain areas of the KOCdh1 mice, which causes dendritic disruption, neurodegeneration and severe microcephaly. Moreover, we have identified a new mutation in Cdh1 (p. Asp187Gly) in humans, which causes microcephaly, epilepsy refractory to treatment and psychomotor retardation. These results confirm that Cdh1 is essential for the correct development of the CNS, since it regulates the establishment of neuronal connections and, with it, neuronal viability during brain development.

Therefore, we have identified the APC/C-Cdh1-FMRP signaling pathway as a key regulator of dendritic stability and synaptic plasticity during CNS postnatal development. Our results show that Cdh1-FMRP axis regulation is essential for brain development, which highlights the relevance of Cdh1 in neuropathologies, such as FXS.


Scientific Production
Magazine Articles 3
Communications at national conferences 2
Communications at international conferences 2


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