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Parkinson's Disease and Related Disorders

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

Pathological phenotype of the familial Parkinson's disease using induced pluripotent stem cells

  • P1-305
  • 太田 悦朗 / Etsuro Ohta:1,2 仁平 友子 / Tomoko Nihira:3 今泉 陽一 / Yoichi Imaizumi:4 赤松 和土 / Wado Akamatsu:4 永井 真貴子 / Makiko Nagai:5 高橋 加代子 / Kayoko Takahashi:6 大山 学 / Manabu Ohyama:7 天谷 雅行 / Masayuki Amagai:7 水野 美邦 / Yoshikuni Mizuno:3 望月 秀樹 / Hideki Mochizuki:8 小幡 文弥 / Fumiya Obata:1,2 岡野 栄之 / Hideyuki Okano:4 
  • 1:北里大・医療衛生・免疫学 / Dept Immunol, Kitasato Univ of Allied Health Sci, Kanagawa, Japan 2:北里大・医療衛生・細胞デザイン研究開発センター / R & D Center for Cell Design, Institute for Regenerative Medicine and Cell Design, Kitasato Univ, Kanagawa, Japan 3:北里大・神経再生医療学講座 / Dept Neuro-Regenerative Medicine, Kitasato Univ, Kanagawa, Japan 4:慶應義塾大・医・生理学 / Dept Physiol, Keio Univ Sch of Med, Tokyo, Japan 5:北里大・医・神経内科学 / Dept Neurology, Kitasato Univ, Kanagawa, Japan 6:北里大学病院・臨床検査部 / Dept Med Lab, Kitasato Univ Hospital, Kanagawa, Japan 7:慶應義塾大・医・皮膚科学 / Dept Dermatol, Keio Univ Sch of Med, Tokyo, Japan 8:大阪大・医・神経内科学 / Dept Neurol, Osaka Univ Sch of Med, Osaka, Japan 

Leucine-rich repeat kinase 2 (LRRK2) is the causative molecule of the autosomal dominant hereditary form of Parkinson's disease (PD), PARK8, which was originally defined in a study of a Japanese family (the Sagamihara family) harboring the I2020T mutation in the kinase domain. Although a number of reported studies have focused on cell death mediated by mutant LRRK2, details of the pathogenetic effect of LRRK2 remain completely unknown. In the present study, to elucidate the mechanism of neurodegeneration in PD caused by LRRK2, we generated induced pluripotent stem cells (iPSCs) derived from dermal fibroblasts isolated from two PARK8 patients (LA and LB) in the Sagamihara family using retroviruses carrying Oct4, Sox2, Klf4, and c-Myc genes, as previously described. To evaluate the iPSCs lines established from the patient, we characterized their properties. All of the patient iPSCs lines demonstrated differentiation of all three germ layers spontaneously in vivo, and maintained a normal karyotype. We found that more than 80% of the differentiated cells were positive for βIII-tubulin (a neuron-specific marker). We also found that I2020T mutant LRRK2 iPSCs-derived neurons released less dopamine than control iPSCs-derived neurons. Furthermore, we demonstrated that patient iPSCs-derived neurons had a lower phospho-AKT1 level than control iPSCs-derived neurons, and that the former showed an increased incidence of apoptosis relative to the controls. These results suggest that I2020T LRRK2-iPSCs could be a promising new tool for reproducing the pathology of PD in the brain caused by the I2020T mutation, and applicable as a model in studies of targeted therapeutics.

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