Advanced search
Start date

Investigation of cellular and molecular mechanisms associated with the deficiency in the ubiquitin-conjugating enzyme UBE2A


The activity of enzymes in the protein ubiquitination pathway is critical for synaptic development and function, as well as for mitochondrial and cellular homeostasis, and dysregulation of these enzymes has been increasingly associated with neurodevelopmental and neurodegenerative diseases. Intellectual Disability (ID) is characterized by cognitive limitations and deficits in adaptive behavior, which typically persist throughout the individual's life, representing a socioeconomic and health problem. The spectrum of DI mutations currently includes a variety of proteins from the protein ubiquitination pathway which, in addition to signaling proteins for degradation, may also regulate other cellular processes. UBE2A is an E2 ubiquitin conjugating enzyme of this pathway and has been reported to act in mechanisms of DNA repair, genomic integrity maintenance, regulation of p53 expression, removal of dysfunctional mitochondria and regulation of proteasome activity. E2 enzymes generally determine the type of ubiquitination signal and therefore the fate of the substrate protein. Mutations in the UBE2A gene have been associated with the X-linked ID type Nascimento syndrome. A new missense mutation in UBE2A, Q93E, located at the enzyme's catalytic site, was identified in a family of Brazilian patients with moderate ID. This mutation affects the enzyme's ability to transfer ubiquitin to lysine, thereby inhibiting product formation. At LNBio/CNPEM, we have generated a knockin mouse model carrying this variant in UBE2A using the CRISPR/Cas9 technology and preliminary tests characterizing the model pointed to alterations in cerebral cytoarchitecture and synaptic transmission. It was also observed that these changes are reflected in the behavior of the UBE2A Q93E animal. To obtain a better understanding of the mechanisms by which UBE2A deficiency induces the mentioned alterations and contributes to DI, we propose to carry out studies on mitochondrial morphology and function, identification of interaction partners, transcriptome and global proteome of ubiquitination with brain tissue of the UBE2A murine model, as well as carry out the validation of targets and affected cellular pathways. These results may bring important contributions to new strategies for using UBE2A and related proteins as a potential therapeutic target for neuronal diseases. (AU)

Articles published in Agência FAPESP Newsletter about the research grant:
Articles published in other media outlets (0 total):
More itemsLess items

Please report errors in scientific publications list by writing to: