7月4日，Sci Transl Med雜志報道了利用疾病來源誘導多能干細胞研究帕金森氏病氧化應激和線粒體功能障礙的最新進展,。
帕金森氏?。≒D）是一種常見的神經(jīng)退行性疾病,，由導致大腦黑質(zhì)紋狀體多巴胺能通路變性的遺傳和環(huán)境因素造成的。研究者獲得了來源于帕金森氏癥患者和攜帶PINK1基因（PTEN基因誘導的假定激酶1）和LRRK2（富含亮氨酸的重復激酶2）基因突變的癥狀發(fā)生前個人的誘導多能干細胞（iPS細胞）,，并將這些細胞分別誘導產(chǎn)生了相應的神經(jīng)細胞,。研究者進而分析比較了這些神經(jīng)細胞與健康對照組神經(jīng)細胞的異同。
研究者測量了這些iPS細胞來源的神經(jīng)細胞線粒體反應幾個方面的指標,，包括產(chǎn)生的活性氧族，線粒體呼吸,，質(zhì)子泄漏,，線粒體在神經(jīng)細胞內(nèi)的運動,。他們還發(fā)現(xiàn)輔酶Q10，雷帕霉素,，或LRRK2的激酶抑制劑GW5074可使來源于家族性帕金森氏癥患者和高危個體iPS細胞的線粒體功能障礙獲得補救,。
對源于攜帶不同基因突變IPS細胞的神經(jīng)細胞進行線粒體反應分析，為研究不同家族性PD細胞水平發(fā)病機制的共性提供了新的啟示,。這同時也突出了這種神經(jīng)退行性疾病中的氧化應激和線粒體功能障礙的重要性,。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
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Pharmacological Rescue of Mitochondrial Deficits in iPSC-Derived Neural Cells from Patients with Familial Parkinson’s Disease
Oliver Cooper1,*,?,Hyemyung Seo1,*,??,Shaida Andrabi2,?,Cristina Guardia-Laguarta3,?,John Graziotto4,?,Maria Sundberg1,?,Jesse R. McLean1,?,Luis Carrillo-Reid5,?,Zhong Xie5,?,Teresia Osborn1,?,Gunnar Hargus1,?,Michela Deleidi1,?,Tristan Lawson1,?,Helle Bogetofte1,?,Eduardo Perez-Torres1,?,Lorraine Clark3,?,Carol Moskowitz3,?,Joseph Mazzulli4,?,Li Chen2,?,Laura Volpicelli-Daley6,?,Norma Romero3,?,Houbo Jiang7,?,Ryan J. Uitti8,?,Zhigao Huang9,Grzegorz Opala10,Leslie A. Scarffe2,?,Valina L. Dawson2,?,Christine Klein11,Jian Feng7,?,Owen A. Ross8,?,John Q. Trojanowski6,?,Virginia M.-Y. Lee6,?,Karen Marder3,?,D. James Surmeier5,?,Zbigniew K. Wszolek8,?,Serge Przedborski3,?,Dimitri Krainc4,?,Ted M. Dawson2,? andOle Isacson1
Parkinson’s disease (PD) is a common neurodegenerative disorder caused by genetic and environmental factors that results in degeneration of the nigrostriatal dopaminergic pathway in the brain. We analyzed neural cells generated from induced pluripotent stem cells (iPSCs) derived from PD patients and presymptomatic individuals carrying mutations in the PINK1 (PTEN-induced putative kinase 1) and LRRK2 (leucine-rich repeat kinase 2) genes, and compared them to those of healthy control subjects. We measured several aspects of mitochondrial responses in the iPSC-derived neural cells including production of reactive oxygen species, mitochondrial respiration, proton leakage, and intraneuronal movement of mitochondria. Cellular vulnerability associated with mitochondrial dysfunction in iPSC-derived neural cells from familial PD patients and at-risk individuals could be rescued with coenzyme Q10, rapamycin, or the LRRK2 kinase inhibitor GW5074. Analysis of mitochondrial responses in iPSC-derived neural cells from PD patients carrying different mutations provides insight into convergence of cellular disease mechanisms between different familial forms of PD and highlights the importance of oxidative stress and mitochondrial dysfunction in this neurodegenerative disease.
