Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling.
Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling.
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DOI：
10.1093/brain/awn334
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发表时间：
2009-02
期刊：
影响因子：
14.5
通讯作者：
Kotter, Mark R.
中科院分区：
文献类型：
--
作者：
Baer, Alexandra S.;Syed, Yasir A.;Kang, Sung Ung;Mitteregger, Dieter;Vig, Raluca;Ffrench-Constant, Charles;Franklin, Robin J. M.;Altmann, Friedrich;Lubec, Gert;Kotter, Mark R.
关键词：
少突胶质细胞前体细胞 (OPC) 分化失败在很大程度上导致慢性脱髓鞘疾病中髓鞘再生（髓鞘再生）失败。尽管这种失败的原因尚不完全清楚，但一些证据表明脱髓鞘后出现的因素会特异性抑制能够产生髓鞘再生少突胶质细胞的细胞的分化。我们之前已经证明，脱髓鞘产生的髓鞘碎片通过抑制 OPC 分化来抑制髓鞘再生，并且这种抑制作用与髓鞘蛋白有关。在本研究中，我们通过对 CM 和 HighQ 柱色谱法制备的抑制蛋白组分进行蛋白质组学分析，然后使用 Nano-HPLC-ESI-Q-TOF 质谱法进行 BN/SDS/SDS-PAGE 凝胶分离，缩小了潜在候选蛋白质的范围。我们发现，髓磷脂介导的 OPC 分化的抑制作用受到 Fyn-RhoA-ROCK 信号传导以及蛋白激酶 C (PKC) 信号传导的调节。我们证明，药理学或 siRNA 介导的 RhoA-ROCK-II 和/或 PKC 信号传导抑制可以在髓磷脂存在的情况下诱导 OPC 分化。我们的研究结果提供了髓鞘质（与脱髓鞘病变相关的 OPC 分化抑制介质）与适合药理学操作的特定信号通路之间的机制联系，因此对于未来旨在增强中枢神经系统髓鞘再生的策略具有重要的潜在价值。
Failure of oligodendrocyte precursor cell (OPC) differentiation contributes significantly to failed myelin sheath regeneration (remyelination) in chronic demyelinating diseases. Although the reasons for this failure are not completely understood, several lines of evidence point to factors present following demyelination that specifically inhibit differentiation of cells capable of generating remyelinating oligodendrocytes. We have previously demonstrated that myelin debris generated by demyelination inhibits remyelination by inhibiting OPC differentiation and that the inhibitory effects are associated with myelin proteins. In the present study, we narrow down the spectrum of potential protein candidates by proteomic analysis of inhibitory protein fractions prepared by CM and HighQ column chromatography followed by BN/SDS/SDS–PAGE gel separation using Nano-HPLC-ESI-Q-TOF mass spectrometry. We show that the inhibitory effects on OPC differentiation mediated by myelin are regulated by Fyn-RhoA-ROCK signalling as well as by modulation of protein kinase C (PKC) signalling. We demonstrate that pharmacological or siRNA-mediated inhibition of RhoA-ROCK-II and/or PKC signalling can induce OPC differentiation in the presence of myelin. Our results, which provide a mechanistic link between myelin, a mediator of OPC differentiation inhibition associated with demyelinating pathologies and specific signalling pathways amenable to pharmacological manipulation, are therefore of significant potential value for future strategies aimed at enhancing CNS remyelination.
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DOI：
10.1016/s0165-3806(03)00096-8
发表时间：
2003-06-12
期刊：
DEVELOPMENTAL BRAIN RESEARCH
影响因子：
--
作者：
Abe, K;Misawa, M
通讯作者：
Misawa, M
影响因子：
6.2
作者：
Cohen, G;Makranz, C;Rotshenker, S
通讯作者：
Rotshenker, S
影响因子：
4.7
作者：
BYERS, DM;PALMER, FBSC;COOK, HW
通讯作者：
COOK, HW
影响因子：
64.8
作者：
FFRENCHCONSTANT, C;RAFF, MC
通讯作者：
RAFF, MC
影响因子：
14.5
作者：
Garbern, JY;Yool, DA;Griffiths, IR
通讯作者：
Griffiths, IR