Functional divergence of the synapsin family in glioblastoma: Synapsin III as a candidate differentiation-restoring...

Glioblastoma (GBM) remains an aggressive adult primary brain tumor despite surgery, radiotherapy and temozolomide-based chemotherapy, partly because glioblastoma stem cells (GSCs) retain self-renewal capacity, lineage plasticity and therapeutic resistance. Cancer neuroscience has shown that glioma cells receive activity-dependent neuronal signals and exploit neural circuits to support tumor growth and invasion. Synaptic proteins may therefore regulate both neuron-glioma communication and tumor-cell state. Synapsin I, II, and III share conserved N-terminal domains but differ in C-terminal architecture, developmental expression and physiological function. An emerging model of functional divergence in GBM is supported by a recent preclinical study comparing Synapsin III with Synapsin I and II. In the tested GSC models, increasing Synapsin III promoted a neuronal-like differentiated phenotype through a neuregulin 3 (NRG3)-JAG1-NOTCH1 mechanism, with reduced stemness and proliferative growth. This review integrates structural, physiological and GBM-focused evidence to examine how the developmental functions of Synapsin III may be repurposed in malignant stem-like cells. Independent replication, durable loss of tumorigenicity and tumor-selective delivery are priorities for translation. Synapsin III is a candidate differentiation-restoring node whose clinical relevance remains to be established.