A research team led by the University of Aveiro (UA), comprising scientists from UA, the Centre for Innovative Biomedicine and Biotechnology (CiBB)/Center for Neuroscience and Cell Biology of the University of Coimbra (CNC-UC), and the University of Beira Interior, has identified a previously unknown role for the protein STEP (Striatal-Enriched Protein Tyrosine Phosphatase) in the development and function of connections between neurons. The findings could contribute to future therapeutic strategies for Fragile X syndrome, the most common inherited cause of intellectual disability and one of the leading genetic causes of autism.
Until now, STEP was known primarily for its role in regulating postsynaptic mechanisms. However, its involvement in the early stages of synapse formation—the specialised structures through which neurons communicate—remained poorly understood. The new study, published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), one of the world's most prestigious multidisciplinary scientific journals, reveals that this protein acts as a molecular “brake” on the development of nerve terminals, limiting synapse maturation and the efficiency of neuronal signal transmission.
Using both in vitro and in vivo experimental models, researchers Joel Pires and Ramiro Almeida, from the Institute of Biomedicine and the Department of Medical Sciences at the University of Aveiro, in collaboration with researchers from CiBB/CNC-UC (Diogo Tomé, Elisa Corti and Miranda Mele) and the University of Beira Interior, demonstrated that reducing or inhibiting STEP activity promotes the organisation of proteins involved in the storage and release of neurotransmitters, thereby increasing the formation of functional synapses.
The results also show that the absence of STEP enhances neuronal excitability and synchronisation across neuronal networks, both indicators of more effective communication between nerve cells. According to the authors, this effect is driven by the preservation of molecular mechanisms that support the assembly of the structures responsible for neurotransmitter release.
Particularly significant is the finding that STEP inhibition was able to correct defects in synapse formation in neurons carrying mutations associated with Fragile X syndrome. This discovery suggests that alterations in STEP activity may contribute to the synaptic dysfunctions that characterise the disorder.
The researchers therefore conclude that STEP plays a central role in regulating neuronal communication and that its inhibition could represent a promising therapeutic strategy for restoring synaptic function in people with Fragile X syndrome.
According to Ramiro Almeida, who led the study, these findings may have important medium- and long-term implications. “By identifying STEP as a regulator of synapse formation, this work opens up new opportunities to better understand disorders in which neuronal communication is impaired, such as Fragile X syndrome and, potentially, other neurodevelopmental disorders”, he says. “In the longer term, this knowledge could contribute to the development of new therapeutic strategies aimed at restoring or improving neuronal connectivity”, he adds.
According to the researcher, the study provides new insights into how the brain builds its communication networks and how this process can go awry in disease. “This knowledge is essential for designing more targeted therapies to correct synaptic dysfunction in the future”, he concludes.
The study advances our understanding of the mechanisms underlying the formation of neuronal networks and opens new avenues for the development of targeted therapies for neurodevelopmental disorders.
The study “The tyrosine phosphatase STEP is a developmental suppressor of synaptogenesis”, published in PNAS jornal in june, is available here.
