Construction and Pharmacological Evaluation of a Novel Parkinson's Disease Mouse Model
10.13241/j.cnki.pmb.2025.13.005
- VernacularTitle:一种新型帕金森疾病小鼠模型的构建及药效评估
- Author:
Shan LIN
1
;
Meng-meng XIE
;
Wen ZENG
;
Zhu ZHU
;
Ying-shan CHEN
;
Tao WANG
;
Rui FENG
Author Information
1. 江苏集萃药康生物科技股份有限公司 江苏南京 210000
- Publication Type:Journal Article
- Keywords:
Parkinson's disease;
Mouse model;
E46K mutation;
Gene therapy
- From:
Progress in Modern Biomedicine
2025;25(13):2118-2129
- CountryChina
- Language:Chinese
-
Abstract:
Objective:This study constructed a mouse model carrying the human SNCA gene with E46K and A53T double mutations through transgenic technology,providing a suitable experimental animal model for drug screening,safety evaluation,pathogenesis research of Parkinson's disease,and studies on neurodegenerative diseases associated with abnormal α-synuclein aggregation.Methods:Using transgenic techniques,we introduced the human SNCA gene with the E46K and A53T mutations into the C57BL/6J mouse genome.These mutations are associated with familial PD and are known to promote α-Synuclein aggregation and neurotoxicity.The resulting B6-hSNCA E46K/A53T transgenic mice were systematically evaluated through behavioral tests to assess motor dysfunction,immunohistochemistry to characterize α-Synuclein pathology,and Western blotting to quantify molecular changes.Additionally,the therapeutic potential of glial cell line-derived neurotrophic factor(GDNF)delivered via adeno-associated virus(AAV)was assessed.Results:The B6-hSNCA E46KA53T double-mutant mice exhibitα-Synuclein aggregation in brain regions such as the cortex,brainstem,and cerebellum starting from 1-months-old.Phosphorylated α-Synuclein protein at serine 129 is detected in regions including the cortex and hippocampus.By 2-months-old,these mice begin to show significant declines in limb strength and motor coordination,as evidenced by grip strength and rotarod tests,displaying motor impairments reminiscent of Parkinson's disease.From 3-months-old,high-performance liquid chromatography(HPLC)reveals a reduction in dopamine and its metabolites in the striatum.Following treatment with AAV-GDNF injection,the mice demonstrate partial improvement in motor behaviors,as observed in rotarod and grip strength behavioral tests.Conclusion:The B6-hSNCA E46KA53T double-mutant mouse model effectively simulates the onset and progression of Parkinson's disease,demonstrating high clinical relevance.This model not only serves as a valuable tool for investigating the pathogenesis of Parkinson's disease but also provides a critical experimental platform for screening and safety evaluation of drugs targeting abnormal α-Synuclein aggregation.It holds significant potential for advancing the development of early diagnostic methods and targeted therapeutic strategies for Parkinson's disease.
