Induction of heat shock protein 70 (Hsp70) prevents neuregulin-induced demyelination by enhancing the proteasomal clearance of c-Jun
Induction of heat shock protein 70 (Hsp70) prevents neuregulin-induced demyelination by enhancing the proteasomal clearance of c-Jun
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DOI：
10.1042/20120047
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发表时间：
2012-01-01
期刊：
影响因子：
4.7
通讯作者：
Dobrowsky, Rick T.
中科院分区：
文献类型：
--
作者：
Li, Chengyuan;Ma, Jiacheng;Dobrowsky, Rick T.
调节分子伴侣正在成为治疗与蛋白质聚集、DPN（糖尿病周围神经病变）和可能的脱髓鞘神经病变相关的神经退行性疾病的有吸引力的方法。KU-32 [N-（7-（（2 R，3R，4S，5 R）-3，4-二羟基-5-甲氧基-6，6-二甲基-四氢-2H-吡喃-2-基氧基）-8-甲基-2-氧代-2H-色烯-3-基）乙酰胺]是一种Hsp 90（热休克蛋白90）的小分子抑制剂，可逆转DPN中与有髓纤维功能障碍相关的感觉缺陷。此外，KU-32防止了通过用NRG 1（神经调节蛋白-1 1型）处理有髓鞘SC（许旺细胞）-DRG（背根神经节）感觉神经元共培养物诱导的有髓鞘节间的损失。由于KU-32以Hsp 70依赖的方式减少NRG 1诱导的脱髓鞘，因此本研究的目的是阐明Hsp 70如何与预防脱髓鞘机制相关。p42/p44 MAPK（丝裂原活化蛋白激酶）的激活和转录因子c-Jun的诱导作为髓鞘形成的负调节剂。NRG 1激活MAPK，诱导c-Jun表达，并促进从WT（野生型）和Hsp 70 KO（敲除）小鼠分离的DRG外植体中髓鞘节段的丢失。尽管KU-32没有阻断MAPK的激活，但它阻断了c-Jun的诱导，并防止WT小鼠中有髓鞘节段的丢失。相比之下，KU-32不能阻止来自Hsp 70 KO小鼠的外植体中c-Jun的NRG 1依赖性诱导和髓鞘节段的损失。从WT或Hsp 70 KO小鼠制备的有髓鞘DRG外植体中Hsp 70的过表达足以阻断c-Jun的诱导和NRG 1诱导的髓鞘段的损失。最后，抑制蛋白酶体阻止KU-32降低c-Jun水平。总的来说，这些数据支持Hsp 70诱导足以通过增强c-Jun的蛋白酶体降解来防止NRG 1诱导的脱髓鞘。
Modulating molecular chaperones is emerging as an attractive approach to treat neurodegenerative diseases associated with protein aggregation, DPN (diabetic peripheral neuropathy) and possibly, demyelinating neuropathies. KU-32 [N-(7-((2R, 3R, 4S, 5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)acetamide] is a small molecule inhibitor of Hsp90 (heat shock protein 90) and reverses sensory deficits associated with myelinated fibre dysfunction in DPN. Additionally, KU-32 prevented the loss of myelinated internodes induced by treating myelinated SC (Schwann cell)-DRG (dorsal root ganglia) sensory neuron co-cultures with NRG1 (neuregulin-1 Type 1). Since KU-32 decreased NRG1-induced demyelination in an Hsp70-dependent manner, the goal of the current study was to clarify how Hsp70 may be mechanistically linked to preventing demyelination. The activation of p42/p44 MAPK (mitogen-activated protein kinase) and induction of the transcription factor c-Jun serve as negative regulators of myelination. NRG1 activated MAPK, induced c-Jun expression and promoted a loss of myelin segments in DRG explants isolated from both WT (wild-type) and Hsp70 KO (knockout) mice. Although KU-32 did not block the activation of MAPK, it blocked c-Jun induction and protected against a loss of myelinated segments in WT mice. In contrast, KU-32 did not prevent the NRG1-dependent induction of c-Jun and loss of myelin segments in explants from Hsp70 KO mice. Overexpression of Hsp70 in myelinated DRG explants prepared from WT or Hsp70 KO mice was sufficient to block the induction of c-Jun and the loss of myelin segments induced by NRG1. Lastly, inhibiting the proteasome prevented KU-32 from decreasing c-Jun levels. Collectively, these data support that Hsp70 induction is sufficient to prevent NRG1-induced demyelination by enhancing the proteasomal degradation of c-Jun.