Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo: implications for PD therapeutics.
Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo: implications for PD therapeutics.
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DOI：
10.1371/journal.pone.0092098
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
McLean PJ
中科院分区：
文献类型：
--
作者：
Dimant H;Zhu L;Kibuuka LN;Fan Z;Hyman BT;McLean PJ
帕金森病是一种神经退行性疾病，其特征在于路易体，一种主要由聚集的α突触核蛋白组成的病理标志。越来越多的证据表明较小的寡聚体聚集体与疾病病因学的关联，并且许多治疗方法旨在抑制和减少聚集过程。分子伴侣和共伴侣在蛋白质稳态中起关键作用，并且具有作为抑制α突触核蛋白相关毒性的治疗剂的潜力。在这里，我们使用基因治疗的方法来评估的Hsp 70共伴侣CHIP（C-末端Hsp 70相互作用蛋白）作为治疗候选人的适用性，并检查其在体内的α突触核蛋白聚集体的直接影响。利用一种新的病毒载体介导的大鼠模型直接检测α突触核蛋白聚集体，我们表明，CHIP可以介导α突触核蛋白聚集体在体内的降解。然而，我们的研究还表明，CHIP可能会潜在地降解酪氨酸羟化酶，这将损害CHIP作为帕金森病治疗方法的适用性。
Parkinson's disease is a neurodegenerative disorder characterized by Lewy bodies, a pathological hallmark comprised mostly of aggregated alpha synuclein. Accumulating evidence demonstrates the association of smaller oligomeric aggregates to disease etiology and many therapeutic approaches are aimed at inhibiting and reducing the aggregation process. Molecular chaperones and co-chaperones play a key role in protein homeostasis and have potential as therapeutics to inhibit alpha synuclein associated toxicity. Here we use a gene therapy approach to evaluate the applicability of the Hsp70 co-chaperone CHIP (C-terminal Hsp70 interacting protein) as a therapeutic candidate and examine its direct effect on alpha synuclein aggregates in vivo. Utilizing a novel viral vector mediated rat model to directly detect alpha synuclein aggregates, we show that CHIP can mediate the degradation of alpha synuclein aggregates in vivo. However, our studies also reveal that CHIP may potentially degrade tyrosine hydroxylase which would compromise the applicability of CHIP as a therapeutic approach for Parkinson's disease.
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影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
DOI：
10.1097/00005072-199804000-00005
发表时间：
1998-04-01
影响因子：
3.2
作者：
Irizarry, MC;Growdon, W;Hyman, BT
通讯作者：
Hyman, BT
影响因子：
4.7
作者：
Sahara, N;Murayama, M;Takashima, A
通讯作者：
Takashima, A
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：
Tetzlaff, Julie E.;Putcha, Preeti;McLean, Pamela J.
通讯作者：
McLean, Pamela J.