Reduced synaptic activity and dysregulated extracellular matrix pathways are common phenotypes in midbrain neurons derived from sporadic and mutation-associated Parkinson’s disease patients
Reduced synaptic activity and dysregulated extracellular matrix pathways are common phenotypes in midbrain neurons derived from sporadic and mutation-associated Parkinson’s disease patients
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突触活性降低和细胞外基质通路失调是散发性和突变相关帕金森病患者中脑神经元的常见表型
DOI：
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
F. Gage
中科院分区：
文献类型：
--
作者：
Shani Stern;Shong Lau;A. Manole;Idan Rosh;Menahem Percia;Ran Ben;M. Shokhirev;F. Qiu;Simon T. Schafer;A. Mansour;Tchelet Stern;Pola Ofer;Yam Stern;Ana M. Diniz;L. Moore;Ritu Nayak;Aidan Aicher;Amanda J. Rhee;Thomas Wong;Thao Nguyen;Sara B. Linker;B. Winner;Beatriz C. Freitas;E. Jones;C. Bardy;A. Brice;J. Winkler;M. C. Marchetto;F. Gage
在过去的十年中，已经确定了导致帕金森病（PD）的几种突变。这些占PD病例的15-25%;其余病例被认为是散发的。目前，人们普遍认为PD不是一种单一的疾病，而是一系列具有一些常见表型的疾病。虽然存在一些导致PD突变的啮齿动物模型，但由于缺乏细胞模型，对PD散发形式的研究滞后。在我们的研究中，我们区分PD患者衍生的多巴胺能（DA）神经元从诱导多能干细胞（iPSC）的几个PD引起的突变，以及从散发性PD患者。引人注目的是，我们观察到一个共同的神经生理表型：来自PD患者的神经元与来自健康对照的神经元相比，突触电流的速率严重降低。虽然之前已经研究了SNCA和LRRK 2等基因突变与突触传递减少之间的关系，但在这里，我们证明神经元突触的发病机制是PD的一般表型。RNA测序结果的分析显示了不同突触机制以及其他受影响的途径（如细胞外基质相关途径）中基因表达的变化。这些失调的途径中的一些是所有PD患者（单基因或特发性）共有的。因此，我们的数据显示，中央和收敛到PD的变化，并提出了强烈的参与PD的病理生理学的四方突触。
Several mutations that cause Parkinson’s disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: Neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, shows changes that are central and convergent to PD and suggests a strong involvement of the tetra-partite synapse in PD pathophysiology.
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影响因子：
14.5
作者：
Eslamboli, Andisheh;Romero-Ramos, Marina;Kirik, Deniz
通讯作者：
Kirik, Deniz
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
DOI：
10.1016/s0165-3806(96)00210-6
发表时间：
1997-03
期刊：
Brain research. Developmental brain research
影响因子：
--
作者：
G. Withers;J. George;G. Banker;D. F. Clayton
通讯作者：
G. Withers;J. George;G. Banker;D. F. Clayton
影响因子：
4.1
作者：
Puschmann A;Ross OA;Vilariño-Güell C;Lincoln SJ;Kachergus JM;Cobb SA;Lindquist SG;Nielsen JE;Wszolek ZK;Farrer M;Widner H;van Westen D;Hägerström D;Markopoulou K;Chase BA;Nilsson K;Reimer J;Nilsson C
通讯作者：
Nilsson C
影响因子：
3.7
作者：
Shin, Narae;Jeong, Hyerhan;Seol, Wongi
通讯作者：
Seol, Wongi