7月4日，Sci Transl Med雜志報(bào)道了利用疾病來(lái)源誘導(dǎo)多能干細(xì)胞研究帕金森氏病氧化應(yīng)激和線(xiàn)粒體功能障礙的最新進(jìn)展,。
帕金森氏?。≒D）是一種常見(jiàn)的神經(jīng)退行性疾病,，由導(dǎo)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(lái)源于帕金森氏癥患者和攜帶PINK1基因（PTEN基因誘導(dǎo)的假定激酶1）和LRRK2（富含亮氨酸的重復(fù)激酶2）基因突變的癥狀發(fā)生前個(gè)人的誘導(dǎo)多能干細(xì)胞（iPS細(xì)胞）,，并將這些細(xì)胞分別誘導(dǎo)產(chǎn)生了相應(yīng)的神經(jīng)細(xì)胞,。研究者進(jìn)而分析比較了這些神經(jīng)細(xì)胞與健康對(duì)照組神經(jīng)細(xì)胞的異同。
研究者測(cè)量了這些iPS細(xì)胞來(lái)源的神經(jīng)細(xì)胞線(xiàn)粒體反應(yīng)幾個(gè)方面的指標(biāo),，包括產(chǎn)生的活性氧族,，線(xiàn)粒體呼吸,，質(zhì)子泄漏,，線(xiàn)粒體在神經(jīng)細(xì)胞內(nèi)的運(yùn)動(dòng)。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(lái)源于家族性帕金森氏癥患者和高危個(gè)體iPS細(xì)胞的線(xiàn)粒體功能障礙獲得補(bǔ)救。
對(duì)源于攜帶不同基因突變IPS細(xì)胞的神經(jīng)細(xì)胞進(jìn)行線(xiàn)粒體反應(yīng)分析,，為研究不同家族性PD細(xì)胞水平發(fā)病機(jī)制的共性提供了新的啟示,。這同時(shí)也突出了這種神經(jīng)退行性疾病中的氧化應(yīng)激和線(xiàn)粒體功能障礙的重要性。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
PMC:
PMID:
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.
