CNS neuroscience & therapeutics · 2026
SYNGR3 Accelerates α-Synuclein Aggregation and Neurodegeneration in Parkinson's Disease.
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Wang Xin, Yang Jiaolong, Wang Ziku, Liu Zhichao, Tan Wei, Zhang Zhentao
Аннотация
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.
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.