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Parkinson's Disease and Related Disorders

開催日 2014/9/13
時間 14:00 - 15:00
会場 Poster / Exhibition(Event Hall B)

Generation of iPS cells haboring GBA heterozygous mutations

  • P3-296
  • 陣上 直人 / Naoto Jingami:1,2 山門 穂高 / Hodaka Yamakado:1 小芝 泰 / Yasushi Koshiba:1,2 大江田 知子 / Tomoko Oeda:3 澤田 秀幸 / Hideyuki Sawada:3 堀田 秋津 / Akitsu Hotta:2 井上 治久 / Haruhisa Inoue:2 高橋 淳 / Jun Takahashi:2 高橋 良輔 / Ryosuke Takahashi:1 
  • 1:京都大学大学院医学研究科臨床神経学 / Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan 2:京都大学iPS細胞研究所 / Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan 3:国立病院機構宇多野病院臨床研究部 / Clinical Research Center, Utano Hospital, Kyoto, Japan 

Idiopathic Parkinson's disease (iPD) is a neurodegenerative disease characterized by the dopaminergic cell loss and the presence of Lewy bodies whose main component is α-synuclein (α-syn). Recently, the heterozygous mutation of glucocerebrosidase (GBA) gene was reported to be the influential genetic risk factor for iPD. GBA is a catalytic enzyme whose substrate is glucocerebroside (GluCer), and homozygous mutation of GBA is responsible for Gaucher disease (GD). Although the precise role of the GBA heterozygous mutation in iPD remains unknown, it is hypothesized that the accumulation of the GluCer by GBA mutation stablizes α-syn oligomer. In addition, α-syn oligomer can affect the intracellular GBA trafficking which causes further GBA depletion. Induced pluripotent stem cells (iPSCs) technology and the recent methodological advances in the differentiation of iPSCs to dopaminergic (DA) neurons enabled us to analyze the DA neurons differentiated from iPSCs of iPD patients. However, the heterogeneity and the variation of genetic background in iPD patients (and the clonal variation of iPSCs from even the same patients) make it difficult to elucidate the phenotypes of iPSCs specific to iPD patients.
We performed genetic screening of GBA hot spots (exon 5 & 10) in 94 PD patients, and identified 2 patients with GBA mutation (L444P and R120W). We generated iPS cells from them. By employing clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) system for correcting these GBA mutations to normal allele, which can be used as an isogenic control for patient-derived iPSCs, we can minimize the effects of the variation of genetic background, although the problem of clonal variations in iPSCs still remains. These patient-derived iPSCs could be a valuable platform for unraveling the pathomechanism of PD, to find the biomarker especially in early or prodromal stage of PD and to develop the drugs for PD.

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