For years, it has been known that mutations in both copies of the HERC2 gene are associated with a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, features of the autism spectrum and movement disorders - characteristics very similar to those of Angelman syndrome, a better-known but equally rare condition. However, the exact function of the affected gene (HERC2) and the molecules with which it interacts remained unclear. Without understanding the biology underlying the syndrome, it was difficult to comprehend how it works and to devise therapeutic strategies to treat it.
Now, a scientific study led by researchers from the University of Barcelona and the Bellvitge Biomedical Research Institute (IDIBELL) at the Bellvitge Campus has studied the role of the HERC2 gene in neurodevelopmental disorders of this type, identifying its key role in the selective degradation of proteins - the "quality control" of proteins within the cell - which is carried out via the proteasome system.
The study, published in the journal Cell Death Discovery , was led by José Luis Rosa, a professor at the UB's Faculty of Medicine and Health Sciences and principal investigator of the Cell Signalling and Bone Biology Group at IDIBELL. The research, with Joan Sala-Gaston and Laura Costa-Sastre as lead authors, marks the first steps towards unravelling the biology of disorders caused by this gene.
A family of genes linked to various neurodevelopmental disorders
Pathogenic variants in the HERC1 and HERC2 genes, which encode E3 ubiquitin ligase enzymes, have been linked to various neurodevelopmental disorders. In the case of HERC1, genetic alterations in both copies of the gene cause a rare syndrome characterized by macrocephaly, dysmorphic facial features and psychomotor retardation. Despite this association with multiple conditions, until now, little information was available on which proteins HERC2 regulates and, therefore, how these alterations contribute to the disease.
Research findings show that the HERC2 protein recognizes protein subunits that have not yen been correctly assembled and targets them for degradation, a process that depends on interaction with chaperone proteins.
"Essentially, the role of HERC2 is to detect defective proteins and tag them with ubiquitin, which indicates they are not properly assembled and must therefore be degraded," explains José Luis Rosa, from the Department of Physiological Sciences at the UB. This mechanism is essential for ensuring the proper assembly of the proteasome and, above all, for maintaining the balance of proteins within the cell. That is why, when HERC2 does not function correctly, this balance is disrupted, proteins that should be degraded accumulate, and proteasome activity is affected," he concludes.
