The beneficial effect of a prolyl oligopeptidase inhibitor, KYP-2047, on alpha-synuclein clearance and autophagy in A30P transgenic mouse.
The beneficial effect of a prolyl oligopeptidase inhibitor, KYP-2047, on alpha-synuclein clearance and autophagy in A30P transgenic mouse.
复制标题
在A30p转基因小鼠中，丙酰寡肽酶抑制剂KYP-2047的有益作用对α-核蛋白清除和自噬的有益作用。
DOI：
10.1016/j.nbd.2014.04.003
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发表时间：
2014-08
影响因子：
6.1
通讯作者：
Myöhänen TT
中科院分区：
文献类型：
--
作者：
Savolainen MH;Richie CT;Harvey BK;Männistö PT;Maguire-Zeiss KA;Myöhänen TT
α-突触核蛋白（aSyn）的错误折叠和聚集最终导致毒性形式的积累，扰乱正常的神经元功能并导致细胞死亡。在帕金森氏病、路易体痴呆和其他突触核蛋白病中可见富含aSyn的包涵体。脯氨酸寡聚肽酶（Prolyl oligopeptidase， PREP）可加速aSyn的聚集过程，抑制PREP可导致细胞模型和转基因aSyn小鼠中aSyn的聚集量减少。在这项研究中，我们研究了5天和28天的PREP抑制剂（KYP-2047）对携带aSyn编码基因点突变的小鼠品系的影响。在PREP抑制后，我们发现高分子量低聚物aSyn减少，同时自噬体标记物LC3BII的量增加，这表明kypp -2047增强了大自噬（自噬）和aSyn清除。此外，kypp -2047治疗28天后，纹状体多巴胺水平显著升高。在细胞培养中，过表达PREP可减少细胞自噬。此外，PREP的抑制使自噬抑制或aSyn过表达引起的自噬标志物（LC3BII和p62）的变化正常化，并诱导自噬的正调节因子beclin 1的表达。综上所述，我们的研究结果表明，PREP抑制通过增加自噬来加速蛋白质聚集体的清除，从而使体内和体外的细胞功能正常化。因此，PREP抑制在突触核蛋白病的治疗中可能具有未来的潜力。
The misfolding and aggregation of α-synuclein (aSyn) eventually leads to an accumulation of toxic forms that disturb normal neuronal function and result in cell death. aSyn rich inclusions are seen in Parkinson’s disease, dementia with Lewy bodies and other synucleinopathies. Prolyl oligopeptidase (PREP) can accelerate the aggregation process of aSyn and the inhibition of PREP leads to a decreased amount of aggregated aSyn in cell models and in aSyn transgenic mice. In this study, we investigated the effect of 5- and 28-day PREP inhibitor (KYP-2047) treatment on a mouse strain carrying a point mutation in the aSyn coding gene. Following PREP inhibition, we found a decrease in high molecular-weight oligomeric aSyn and a concomitant increase in the amount of the autophagosome marker, LC3BII, suggesting enhanced macroautophagy (autophagy) and aSyn clearance by KYP-2047. Moreover, 28-day treatment with KYP-2047 caused significant increases in striatal dopamine levels. In cell culture, overexpression of PREP reduced the autophagy. Furthermore, the inhibition of PREP normalized the changes on autophagy markers (LC3BII and p62) caused by an autophagy inhibition or aSyn overexpression, and induced the expression of beclin 1, a positive regulator of autophagy. Taken together, our results suggest that PREP inhibition accelerates the clearance of protein aggregates via increased autophagy and thus normalizes the cell functions in vivo and in vitro. Therefore, PREP inhibition may have future potential in the treatment of synucleinopathies.
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影响因子：
82.9
作者：
Conway, KA;Harper, JD;Lansbury, PT
通讯作者：
Lansbury, PT
DOI：
10.1016/j.biocel.2013.02.007
发表时间：
2013-05-01
影响因子：
4
作者：
Fu, Lei-lei;Cheng, Yan;Liu, Bo
通讯作者：
Liu, Bo
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
6.1
作者：
Chen, Li;Thiruchelvam, Mona J.;Richfield, Eric K.
通讯作者：
Richfield, Eric K.
影响因子：
2.3
作者：
Airavaara, M;Mijatovic, J;Ahtee, L
通讯作者：
Ahtee, L