Establishment Of α-Synuclein Transgenic Mouse Model Of Parkinson's Disease

Parkinson's disease (PD) is a chronically progressive, age-related and fatal neurological disease. Resting tremor, rigidity, bradykinesia and postural instability characterize PD clinically. It has become one of the major diseases which threaten the health of the seniors. The pathological hall-marks of PD are degeneration and elimination of dopamine neurons in substantia nigra as well as the formation of intracellular inclusion, known as Lewy body (LB).α-Synuclein is the major constituent of Lewy bodies which play an important role in the pathogenesis of Parkinson's disease. Under normal conditions, it is thought to have a role in the modulation of synaptic vesicle turnover and synaptic plasticity. And it is also important in lipid metabolism, signal transduction and vesicle transport. Two missense mutations in theα-synuclein gene (Ala-53→Thr and Ala-30→Pro) have been found in rare autosomal dominant inherited forms of PD. Duplication and triplication in theα-synuclein gene are also causes of PD. Mutation ofα-synuclein can promote the formation of oligomer to increase their neurotoxity. However, the mutation and excessive expression ofα-synuclein is through which molecular mechanism for the occurrence of PD still unclear. Therefore the establishment ofα-synuclein transgenic animal model of Parkinson's disease may provide an important model for research in the future.In order to research the role ofα-synuclein in PD pathogenesis, the humanα-Synuclein wild type gene, A53T mutation and A30P mutation transgenic mice were generated. The PDGF driving vectors expressing theα-Synuclein wild type gene, A53T mutation and A30P mutation were constructed. The transgenic mice were created with the microinjection method. The genotype of transgenic founders and its filial generations were identified by PCR. The expression level of humanα-synuclein was analyzed by RT-PCR and Western blotting. Two humanα-synuclein WT transgenic lines with different expression levels were established. Two humanα-synuclein A53T transgenic lines with different expression levels were established. The three humanα-synuclein A30P transgenic lines with different expression levels were established either. The expression levels of humanα-synuclein in the brains of transgenic mice were analyzed by immunohistochemistry staining. The expression ofα-synuclein was detected in hippocampus, neocortex and substantia nigra of all the 7 lines. The decline in motor performance of transgenic mice was measured by rotating rod experiment. All of the transgenic mice lines showed obviously progressive decline in motor performance, A53T, A30P and SYN-WT transgenic mice were down 45.4%, 46.2% and 45.5% compared with the negative control mice.These results indicate that, we have successfully established humanα-synuclein transgenic mouse model of Parkinson's disease. Although, there are still many unknown mechanisms ofα-synuclein in Parkinson's disease, further research needs to be done, the basis model for the pathogenesis research and drug development of Parkinson's disease could be provided in the future.