ABSTRACT Background and Aims The aggregation of α‐synuclein (α‐syn) is a central event in Parkinson's disease (PD) pathogenesis. However, the cellular factors that initiate and accelerate the process are not fully understood. Synaptogyrin‐3 (SYNGR3) is a synaptic vesicle protein whose role in α‐syn pathology remains unexplored. This study investigated whether SYNGR3 is a key factor triggering the pathological process of PD. Methods This study investigated the expression of SYNGR3 in the brains of transgenic A53T α‐syn mutant mouse line M83 (TgA53T) PD model mice using Western blot. The direct interaction between SYNGR3 and α‐syn was assessed by GST pull‐down assays. This study examined the effect of SYNGR3 on α‐syn aggregation kinetics and fibril stability in vitro through the thioflavin T (Th T) assays and proteinase K (PK) digestion. By overexpressing or knocking down SYNGR3 in HEK‐293 cells stably transfected with α‐syn, primary neurons, and TgA53T mice, the effects of enhanced or deficient function of SYNGR3 on α‐syn pathology, synaptic integrity, mitochondrial function, and motor behavior were evaluated. Results SYNGR3 levels were significantly elevated in an age‐dependent manner in the striatum of TgA53T mice. The study found that SYNGR3 directly interacts with the central region of α‐syn and accelerates its aggregation into fibrils that are more resistant to PK digestion. Overexpression of SYNGR3 exacerbated α‐syn aggregation, synaptic protein loss, mitochondrial dysfunction, and apoptosis in cellular models. In vivo, SYNGR3 intensified α‐syn pathology, dopaminergic neurodegeneration, and PD‐like motor deficits. Conversely, knockdown of SYNGR3 effectively alleviated these pathological and behavioral impairments. Conclusion This study identifies SYNGR3 as a novel and critical promoter of α‐syn aggregation and neurotoxicity. These findings establish SYNGR3 as a key contributor to PD pathogenesis and highlight its potential as a therapeutic target for intervention.
Wang et al. (Sun,) studied this question.