Mutual exacerbation of peroxisome proliferator-activated receptor γ coactivator 1α deregulation and α-synuclein oligomerization.
Mutual exacerbation of peroxisome proliferator-activated receptor γ coactivator 1α deregulation and α-synuclein oligomerization.
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DOI：
10.1002/ana.24294
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发表时间：
2015-01
影响因子：
11.2
通讯作者：
Danzer, Karin M.
中科院分区：
文献类型：
--
作者：
Eschbach, Judith;von Einem, Bjoern;Mueller, Kathrin;Bayer, Hanna;Scheffold, Annika;Morrison, Bradley E.;Rudolph, K. Lenhard;Thal, Dietmar R.;Witting, Anke;Weydt, Patrick;Otto, Markus;Fauler, Michael;Liss, Birgit;McLean, Pamela J.;La Spada, Albert R.;Ludolph, Albert C.;Weishaupt, Jochen H.;Danzer, Karin M.
α-突触核蛋白（α-syn）的聚集和α-syn细胞毒性是散发性和家族性帕金森病（PD）的标志，越来越多的证据表明前原纤维寡聚体和原纤维是PD和相关突触核蛋白病的致病物种。过氧化物酶体增殖物激活受体γ（PPARγ）共激活因子1α（PGC-1α）是线粒体生物合成和细胞能量代谢的关键调节因子，近年来研究发现其与PD的病理生理学有关。尽管对线粒体中PGC-1α的功能进行了广泛的研究，但没有研究表明PGC-1α是否直接影响α-syn的寡聚化或α-syn寡聚体是否影响PGC-1α的表达。在本研究中，我们发现PGC-1α参考基因（RG-PGC-1α）和CNS特异性PGC-1α（CNS-PGC-1α）在人PD脑、A30 P α-syn转基因动物和α-syn寡聚化细胞培养模型中均下调。重要的是，RG-PGC-1α缺陷小鼠的细胞培养物或神经元中RG-PGC-1α和CNS-PGC-1α的下调导致α-syn寡聚化和毒性的强烈诱导。相反，RG-PGC-1α的药理学激活或基因过表达减少了α-syn寡聚化并挽救了α-syn介导的毒性。基于我们的研究结果，我们提出PGC-1α下调和α-syn寡聚化形成恶性循环，从而相互影响和/或增强。我们的数据表明，PGC-1α的恢复是一种有前途的方法，用于开发治疗PD和相关突触核蛋白病的有效药物。
Aggregation of α-synuclein (α-syn) and α-syn cytotoxicity are hallmarks of sporadic and familial Parkinson’s disease (PD) with accumulating evidence that prefibrillar oligomers and protofibrils are the pathogenic species in PD and related synucleinopathies. Peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1α (PGC-1α), a key regulator of mitochondrial biogenesis and cellular energy metabolism, has recently been associated with the pathophysiology of PD. Despite extensive effort on studying the function of PGC-1α in mitochondria, no studies have addressed whether PGC-1α directly influences oligomerization of α-syn or whether α-syn oligomers impact PGC-1α expression. In this study, we found that both PGC-1α reference gene (RG-PGC-1α) and the CNS specific PGC-1α (CNS-PGC-1α) are downregulated in human PD brain, in A30P α-syn transgenic animals, and in a cell culture model for α-syn oligomerization. Importantly, down-regulation of both RG-PGC-1α and CNS-PGC-1α in cell culture or neurons from RG-PGC-1α deficient mice leads to a strong induction of α-syn oligomerization and toxicity. In contrast, pharmacological activation or genetic overexpression of RG-PGC-1α reduced α-syn oligomerization and rescued α-syn mediated toxicity. Based on our results, we propose that PGC-1α downregulation and α-syn oligomerization from a vicious circle thereby influencing and/or potentiating each other. Our data indicate that restoration of PGC-1α is a promising approach for development of effective drugs for the treatment of PD and related synucleinopathies.
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影响因子：
15.1
作者：
Che HV;Metzger S;Portal E;Deyle C;Riess O;Nguyen HP
通讯作者：
Nguyen HP
影响因子：
15.1
作者：
Danzer KM;Kranich LR;Ruf WP;Cagsal-Getkin O;Winslow AR;Zhu L;Vanderburg CR;McLean PJ
通讯作者：
McLean PJ
影响因子：
4.8
作者：
Danzer, Karin M.;Ruf, Wolfgang P.;McLean, Pamela J.
通讯作者：
McLean, Pamela J.
影响因子：
4.8
作者：
Bucciantini, M;Calloni, G;Stefani, M
通讯作者：
Stefani, M
影响因子：
3.4
作者：
Bonen, Arend
通讯作者：
Bonen, Arend