An animal model is essential not only to explore the pathogenesis of Parkinson's disease (PD). However, an appropriate animal model of PD is not available.

Recent genetic studies show that the multiplications or point mutations of alpha-synuclein (alpha-Syn) are responsible for the familial PD. Pathologically, alpha-Syn was found to be as the main component of Lewy bodies that are the hallmark of PD. In addition, recent GWAS-PD (genome-wide association studies in PD) identified the most critical SNP in the alpha-Syn gene. Another important gene is a glucocerebrosidase (GBA) whose homozygous mutation is responsible for Gaucher disease (GD). Recent genetic study suggests that GBA heterozygous mutation is a strong risk factor to idiopathic PD. Although its precise mechanism remains unknown, it is assumed that the accumulation of the GluCer (a substrates of GBA) caused by GBA mutations affects lysosomal function and induced alpha-Syn accumulation. Moreover, alpha-Syn accumulation could affect the intracellular GBA trafficking which results in further GBA depletion and makes a vicious cycle.

Our previous alpha-Syn BAC tg mice that harbor the entire human alpha-Syn gene and its gene expression regulatory regions expressed 2.7-fold amount of alpha-Syn with similar expression pattern to endogeneous alpha-Syn. They manifested decreased anxiety-like behaviors which may reflect non-motor symptoms, however, did not showed obvious motor symptoms or dopaminergic neuronal loss, mainly due to the low expression level of transgenic wild-type alpha-Syn. By utilizing these biochemical interaction of alpha-Syn and GBA in iPD, we crossed alpha -Syn BAC tg mice with GBA heterozygous mice to create novel mice model for iPD. We expect that increased alpha-Syn accumulation by GBA depletion would exacerbate alpha-Syn pathology and finally cause PD symptoms in these mice. Now we are planning to conduct comprehensive battery of behavioural analysis and to perform biochemical pathological analysis in these mice.