Role of STX1A in Parkinson’s disease: evidence, mechanistic hypotheses, and translational perspectives

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by degeneration of substantia nigra dopaminergic neurons, α-synuclein pathology, and widespread synaptic dysfunction. Syntaxin-1A (STX1A), a presynaptic Qa-SNARE protein, is essential for synaptic vesicle fusion and also interacts with proteins involved in ion-channel regulation and neuronal excitability. Several animal, extracellular-vesicle, and peripheral-blood studies have reported reduced STX1A abundance in PD. However, the available evidence is predominantly cross-sectional and does not establish whether STX1A downregulation is a cause of PD pathology, a consequence of neuronal and synaptic loss, or a peripheral correlate of disease. This narrative review critically evaluates evidence linking STX1A to PD and distinguishes experimentally supported observations from mechanistic hypotheses. Potential relationships with calcium dysregulation, mitochondrial injury, ferroptosis, and neuroimmune signaling are discussed as testable models rather than established pathways. Direct evidence connecting STX1A to the gut–brain axis in PD is currently lacking and is therefore considered primarily as a future research direction. The biomarker and therapeutic potential of STX1A remains preliminary because diagnostic performance, disease specificity, longitudinal stability, and causal relevance have not been adequately validated. Future studies using cell-type-specific STX1A manipulation, rescue experiments, electrophysiology, and multicenter longitudinal cohorts are required to define the biological and clinical significance of STX1A in PD.