Higher vulnerability and stress sensitivity of neuronal precursor cells carrying an alpha-synuclein gene triplication.
Higher vulnerability and stress sensitivity of neuronal precursor cells carrying an alpha-synuclein gene triplication.
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DOI：
10.1371/journal.pone.0112413
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Schüle B
中科院分区：
文献类型：
--
作者：
Flierl A;Oliveira LM;Falomir-Lockhart LJ;Mak SK;Hesley J;Soldner F;Arndt-Jovin DJ;Jaenisch R;Langston JW;Jovin TM;Schüle B
帕金森病 (PD) 是一种多因素神经退行性疾病，表现为黑质中多巴胺能神经元和特征性细胞内包涵体（称为路易体）的丧失。遗传倾向，例如 SNCA 基因位点的点突变和拷贝数变异，可导致非常相似的 PD 样神经变性。 α-突触核蛋白表达改变对神经元干细胞完整性和发育潜力的影响在很大程度上尚未被探索，但可能对 PD 表现和疾病进展产生广泛的影响。在这里，我们研究了是否从携带 SNCA 基因基因组三倍体 (SNCA-Tri) 的帕金森病患者诱导多能干细胞衍生的神经元前体细胞 (NPC)。我们的目标是确定这些神经元前体细胞是否已经表现出病理变化和细胞功能受损，这些变化和细胞功能受损可能会使它们在分化为神经变性时容易发生。为了实现这一目标，我们评估了人类 SNCA-Tri NPC 在正常和环境应激条件下的活力和细胞生理学，以模拟体外基因-环境相互作用，这可能在 PD 的起始和进展中发挥作用。人类 SNCA-Tri NPC 显示出总体正常的细胞和线粒体形态，但在生长、活力、细胞能量代谢和应激抵抗力方面显示出显着变化，特别是在受到饥饿或有毒物质挑战时。通过稳定表达的短发夹 RNA (shRNA) 敲低 SNCA-Tri NPC 中的 α-突触核蛋白，导致观察到的表型变化发生逆转。这些数据首次表明，SNCA 基因三倍体等基因改变导致发育适应性下降、衰老加速和神经元细胞损失增加。对这种“干细胞病理学”的观察可能会对神经元网络的质量和数量产生巨大影响，并可能为开发帕金森病神经保护策略提供强大的新工具。
Parkinson disease (PD) is a multi-factorial neurodegenerative disorder with loss of dopaminergic neurons in the substantia nigra and characteristic intracellular inclusions, called Lewy bodies. Genetic predisposition, such as point mutations and copy number variants of the SNCA gene locus can cause very similar PD-like neurodegeneration. The impact of altered α-synuclein protein expression on integrity and developmental potential of neuronal stem cells is largely unexplored, but may have wide ranging implications for PD manifestation and disease progression. Here, we investigated if induced pluripotent stem cell-derived neuronal precursor cells (NPCs) from a patient with Parkinson’s disease carrying a genomic triplication of the SNCA gene (SNCA-Tri). Our goal was to determine if these cells these neuronal precursor cells already display pathological changes and impaired cellular function that would likely predispose them when differentiated to neurodegeneration. To achieve this aim, we assessed viability and cellular physiology in human SNCA-Tri NPCs both under normal and environmentally stressed conditions to model in vitro gene-environment interactions which may play a role in the initiation and progression of PD. Human SNCA-Tri NPCs displayed overall normal cellular and mitochondrial morphology, but showed substantial changes in growth, viability, cellular energy metabolism and stress resistance especially when challenged by starvation or toxicant challenge. Knockdown of α-synuclein in the SNCA-Tri NPCs by stably expressed short hairpin RNA (shRNA) resulted in reversal of the observed phenotypic changes. These data show for the first time that genetic alterations such as the SNCA gene triplication set the stage for decreased developmental fitness, accelerated aging, and increased neuronal cell loss. The observation of this “stem cell pathology” could have a great impact on both quality and quantity of neuronal networks and could provide a powerful new tool for development of neuroprotective strategies for PD.
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影响因子：
4.3
作者：
Csordas, Gyoergy;Hajnoczky, Gyoergy
通讯作者：
Hajnoczky, Gyoergy
影响因子：
4.8
作者：
Liu, Chao;Fei, Erkang;Wang, Guanghui
通讯作者：
Wang, Guanghui
影响因子：
17.1
作者：
Cooper O;Seo H;Andrabi S;Guardia-Laguarta C;Graziotto J;Sundberg M;McLean JR;Carrillo-Reid L;Xie Z;Osborn T;Hargus G;Deleidi M;Lawson T;Bogetofte H;Perez-Torres E;Clark L;Moskowitz C;Mazzulli J;Chen L;Volpicelli-Daley L;Romero N;Jiang H;Uitti RJ;Huang Z;Opala G;Scarffe LA;Dawson VL;Klein C;Feng J;Ross OA;Trojanowski JQ;Lee VM;Marder K;Surmeier DJ;Wszolek ZK;Przedborski S;Krainc D;Dawson TM;Isacson O
通讯作者：
Isacson O
影响因子：
64.8
作者：
Liu, Guang-Hui;Qu, Jing;Suzuki, Keiichiro;Nivet, Emmanuel;Li, Mo;Montserrat, Nuria;Yi, Fei;Xu, Xiuling;Ruiz, Sergio;Zhang, Weiqi;Wagner, Ulrich;Kim, Audrey;Ren, Bing;Li, Ying;Goebl, April;Kim, Jessica;Soligalla, Rupa Devi;Dubova, Ilir;Thompson, James;Yates, John, III;Esteban, Concepcion Rodriguez;Sancho-Martinez, Ignacio;Izpisua Belmonte, Juan Carlos
通讯作者：
Izpisua Belmonte, Juan Carlos
影响因子：
4.8
作者：
Devi, Latha;Raghavendran, Vijayendran;Anandatheerthavarada, Hindupur K.
通讯作者：
Anandatheerthavarada, Hindupur K.