Inhibition of excessive autophagy and mitophagy mediates neuroprotective effects of URB597 against chronic cerebral hypoperfusion.
Inhibition of excessive autophagy and mitophagy mediates neuroprotective effects of URB597 against chronic cerebral hypoperfusion.
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抑制过度自噬和线粒体自噬介导 URB597 对慢性脑灌注不足的神经保护作用
DOI：
10.1038/s41419-018-0755-y
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发表时间：
2018-06-28
影响因子：
9
通讯作者：
Hai J
中科院分区：
文献类型：
--
作者：
Su SH;Wu YF;Wang DP;Hai J
URB597 (URB) has therapeutic potential for treating chronic cerebral hypoperfusion (CCH)-induced neuronal death. The present study investigated the protective effects of URB on autopahgy and mitophagy in a CCH model as well as the underlying mechanisms. The ultrastructural changes were examined by electron microscopy. The mitochondrial membrane potential was assessed by immunofluorescence. The expressions of autophagy-related proteins (beclin-1, p62, and LC3), lysosome-related proteins (CTSD and LAMP1), and mitophagy-related proteins (BNIP3, cyt C and parkin) were evaluated by western blotting, and the interaction of beclin-1 and Bcl-2 were determined by immunoprecipitation. CCH significantly decreased the protein expression of p62, CTSD, and LAMP1 and increased the protein expression of beclin-1, parkin, and BNIP3, the LC3-II to LC3-I ratio, and the release of cyt C from mitochondria to cytoplasm. Furthermore, CCH induced the accumulation of ubiquitinated proteins in PSDs. However, URB significantly reversed these results. Besides, URB significantly inhibited the beclin-1 from beclin-1/Bcl-2 complex to whole-cell lysates. The above results indicate that URB could inhibit impaired autophagy degradation and the disruption of beclin-1/Bcl-2 complex and subsequently cut off BNIP3-cyt C- and parkin-required mitophagy, finally preventing the abnormal excessive autophagy and mitophagy. These findings provide new insights that URB is a promising agent for therapeutic management of CCH.
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