The Impact of VAMP1 Mutations on Synaptic Vesicle Fusion Dynamics in Familial Spastic Disorders

Synaptic vesicle fusion is a process that involves the release of neurotransmitters from synaptic vesicles into the synaptic cleft. VAMP1 is a protein that mediates synaptic vesicle fusion by forming a complex with other proteins on the presynaptic membrane. Mutations in VAMP1 have been recently identified as a cause of a rare form of hereditary spastic paraplegia (HSP), a group of genetic disorders characterized by the gradual development of muscle stiffness and weakness in the lower extremities. We discuss the current knowledge on the structure and function of VAMP1 and its role in synaptic transmission, the clinical features and genetic findings of patients with VAMP1 mutations, the possible pathogenic mechanisms of VAMP1 mutations, such as impaired SNARE complex formation, calcium signaling, and synaptic vesicle recycling and the potential therapeutic strategies for modulating VAMP1 function and restoring synaptic vesicle fusion in hereditary spastic paraplegia patients. We also highlight the research gaps and emerging technologies that may advance the understanding and treatment of VAMP1-related hereditary spastic paraplegia. Furthermore, the review presents some experimental studies that have investigated the molecular and functional consequences of VAMP1 mutations in various models, such as mice, cell lines, or patient-derived samples. These studies have provided evidence for reduced or altered VAMP1 expression, impaired synaptic vesicle fusion and neurotransmitter release, altered synaptic plasticity and excitability, and neuronal degeneration in VAMP1 mutation carriers. These findings suggest that VAMP1 mutations have a significant impact on synaptic vesicle fusion dynamics and neuronal function and may contribute to the pathogenesis and phenotypic variability of hereditary spastic paraplegia.