Synaptotagmin family proteins in neurological disorders: from synaptic vesicle fusion to neuronal vulnerability

The maintenance of neuronal and glial homeostasis depends on precise membrane fusion, vesicular trafficking, receptor turnover and stress-response signaling, processes regulated in part by synaptotagmin (SYT) family proteins. SYTs comprise a family of 17 mammalian membrane-associated regulators with heterogeneous Ca 2 ⁺-binding properties, including several isoforms with atypical or incomplete Ca 2 ⁺-binding sites that may not function as conventional Ca 2 ⁺ sensors. Increasing evidence indicates that dysregulation of specific isoforms contributes to neurological disease through distinct cellular and molecular mechanisms. In this review, we provide a family-wide overview of all 17 mammalian SYTs while examining selected family members in greater depth. We discuss fast-release sensors, including SYT1, SYT2, and SYT9 in defined neuronal populations, activity-dependent and astrocytic secretion involving SYT4, and asynchronous release and synaptic dynamics involving SYT7. We also examine isoforms linked to trafficking control, receptor remodeling, neuroprotection, proteostasis, and neuronal stress-response pathways, including SYT3, SYT10, SYT11, SYT13, and SYT17. We discuss how these isoforms connect membrane-dynamic regulation to neurodevelopmental disorders, neuromuscular junction disease, neurodegeneration, and acquired neurological injury. We also consider the limited human genetic evidence linking SYT14 to an ataxic phenotype. We further highlight evidence-stratified translational implications, including promising but not yet clinically validated CSF biomarker evidence for SYT1, preclinical intervention evidence involving SYT3 and SYT13, and SYT11 as a Parkinson’s disease-related trafficking and proteostasis node. Together, these findings support a cellular and molecular framework in which SYT dysfunction links membrane dynamics, synaptic instability, receptor remodeling, and stress-response failure to neuronal vulnerability and disease translation.