Mitochondrial and Endoplasmic Reticulum Stress Trigger Triglyceride Accumulation in Models of Parkinson's Disease Independent of Mutations in MAPT.
Mitochondrial and Endoplasmic Reticulum Stress Trigger Triglyceride Accumulation in Models of Parkinson's Disease Independent of Mutations in MAPT.
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DOI：
10.3390/metabo13010112
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发表时间：
2023-01-09
期刊：
影响因子：
4.1
通讯作者：
中科院分区：
文献类型：
--
作者：
帕金森病病理的代谢基础尚不清楚。然而，线粒体和内质网应激在多巴胺神经元疾病病因学中的作用已经得到了很好的证实。我们观察了鱼藤酮和tunicamycin诱导的线粒体和内质网应激对野生型和微管相关蛋白tau突变多巴胺神经元代谢的影响。利用RT和TM分别对人分离的iPSCs衍生的多巴胺神经元进行线粒体和内质网应激。通过反相脂质组学分析的分相萃取生成全面的代谢物谱，同时使用HILIC代谢组学测量水相。线粒体和内质网应激均可引起显著的代谢失调，而rt诱导的应激可使野生型和MAPT神经元的代谢谱发生更大的变化。详细分析表明，甘油三酯的积累是两种基因型对两种应激反应中代谢失调的重要驱动因素。虽然结果是相似的，但多巴胺神经元中甘油三酯积累对线粒体和内质网应激的反应机制是非常不同的。因此，提高我们对这些机制如何驱动观察到的甘油三酯积累的理解可能会开辟新的治疗途径。
The metabolic basis of Parkinson’s disease pathology is poorly understood. However, the involvement of mitochondrial and endoplasmic reticulum stress in dopamine neurons in disease aetiology is well established. We looked at the effect of rotenone- and tunicamycin-induced mitochondrial and ER stress on the metabolism of wild type and microtubule-associated protein tau mutant dopamine neurons. Dopamine neurons derived from human isolated iPSCs were subjected to mitochondrial and ER stress using RT and TM, respectively. Comprehensive metabolite profiles were generated using a split phase extraction analysed by reversed phase lipidomics whilst the aqueous phase was measured using HILIC metabolomics. Mitochondrial and ER stress were both shown to cause significant dysregulation of metabolism with RT-induced stress producing a larger shift in the metabolic profile of both wild type and MAPT neurons. Detailed analysis showed that accumulation of triglycerides was a significant driver of metabolic dysregulation in response to both stresses in both genotypes. Whilst the consequence is similar, the mechanisms by which triglyceride accumulation occurs in dopamine neurons in response to mitochondrial and ER stress are very different. Thus, improving our understanding of how these mechanisms drive the observed triglyceride accumulation can potentially open up new therapeutic avenues.
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影响因子：
11.2
作者：
Goris, An;Williams-Gray, Caroline H.;Sawcer, Stephen J.
通讯作者：
Sawcer, Stephen J.
DOI：
10.1016/j.biocel.2013.09.011
发表时间：
2013-12
影响因子：
4
作者：
He, Quan;Wang, Miao;Petucci, Christopher;Gardell, Stephen J.;Han, Xianlin
通讯作者：
Han, Xianlin
影响因子：
13.5
作者：
Fuchs, Claudia D.;Claudel, Thierry;Trauner, Michael
通讯作者：
Trauner, Michael
影响因子：
168.9
作者：
Kalia, Lorraine V.;Lang, Anthony E.
通讯作者：
Lang, Anthony E.
在GBA-N370S帕金森氏菌IPSC衍生的多巴胺神经元中，ER应力和自噬扰动导致细胞外α-突触核蛋白升高。
影响因子：
5.9
作者：
Fernandes HJ;Hartfield EM;Christian HC;Emmanoulidou E;Zheng Y;Booth H;Bogetofte H;Lang C;Ryan BJ;Sardi SP;Badger J;Vowles J;Evetts S;Tofaris GK;Vekrellis K;Talbot K;Hu MT;James W;Cowley SA;Wade-Martins R
通讯作者：
Wade-Martins R