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Parkinson's Disease and Related Disorders

開催日 2014/9/13
時間 11:00 - 12:00
会場 Poster / Exhibition(Event Hall B)

Creating mice models for sporadic Parkinson's disease based on its genetic risk factors

  • P3-295
  • 生野 真嗣 / Masashi Ikuno:1 浅野 剛史 / Takeshi Asano:1 山門 穂高 / Hodaka Yamakado:1 高橋 良輔 / Ryosuke Takahashi:1 
  • 1:京都大学大学院臨床神経学 / Department of Neurology, Kyoto University Graduate School of Medicine 

Parkinson's disease (PD) is a second common neurodegenerative disorder whose precise pathomechanism remains unclear. 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 SNPs in the alpha-Syn gene. Based on these findings, we hypothesized that the alpha-Syn toxicity which is enhanced by its qualitative or quantitative change is important for the development of both familial and idiopathic PD.
In this study, we try to create novel alpha-Syn transgenic (tg) mice with BAC (bacterial artificial chromosome) transgenic technology, because there is no appropriate mice model showing all of the cardinal features of human PD. 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. Therefore, we introduced several mutations to our alpha-Syn BAC construct to enhance the alpha-Syn toxicity. These mutations include the A53T mutation and three risk polymorphisms in Rep1 region and SNP regions of rs11931074 and rs3857059. Now we analyze these mice and we expect these modified alpha-Syn BAC tg mice will express larger amount of alpha-Syn and will be a symptomatic PD mice model in the future.

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