Incorporation of cofilin into rods depends on disulfide intermolecular bonds: implications for actin regulation and neurodegenerative disease.
Incorporation of cofilin into rods depends on disulfide intermolecular bonds: implications for actin regulation and neurodegenerative disease.
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DOI：
10.1523/jneurosci.6020-11.2012
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发表时间：
2012-05-09
期刊：
影响因子：
--
通讯作者：
Bamburg JR
中科院分区：
文献类型：
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作者：
Bernstein BW;Shaw AE;Minamide LS;Pak CW;Bamburg JR
含有等摩尔肌动蛋白和肌动蛋白动力蛋白丝切蛋白的杆状聚集体（“棒”）出现在各种潜在氧化应激后的神经元中：模拟微缺血、丝切蛋白过度表达、暴露于过氧化物、过量谷氨酸或淀粉样蛋白-β肽（Aβd/t）（最具突触毒性的Aβ种类）的二聚体/三聚体形式。这些杆最初是可逆的并具有神经保护作用，但如果它们持续存在于神经突中，突触就会退化，而神经元不会死亡。在此，我们报告了棒的形成取决于丝切蛋白中分子间二硫键的生成的证据。在大鼠 E18 海马神经元中表达的四种 Cys-to-Ala cofilin 突变中，只有无法形成分子间键的突变体 (CC39,147AA) 显着降低了掺入视杆细胞的能力。杆区域显示出异常高的氧化水平。从应激神经元中分离出来的杆状细胞含有二硫苏糖醇敏感的丝切蛋白多聚体形式，主要是二聚体。细胞中丝切蛋白的寡聚化代表了调节丝切蛋白肌动蛋白动力活性的又一种机制，并且可能是突触损失的基础。
Rod-shaped aggregates (“rods”), containing equimolar actin and the actin dynamizing protein cofilin, appear in neurons following a wide variety of potentially oxidative stress: simulated microischemia, cofilin overexpression, and exposure to peroxide, excess glutamate, or the dimer/trimer forms of amyloid-beta peptide (Aβd/t), the most synaptotoxic Aβ species. These rods are initially reversible and neuroprotective, but if they persist in neurites, the synapses degenerate without neurons dying. Herein we report evidence that rod formation depends on the generation of inter-molecular disulfide bonds in cofilin. Of four Cys-to-Ala cofilin mutations expressed in rat E18 hippocampal neurons, only the mutant incapable of forming inter-molecular bonds (CC39,147AA) has significantly reduced ability to incorporate into rods. Rod regions show unusually high oxidation levels. Rods, isolated from stressed neurons, contain dithiothreitol-sensitive multimeric forms of cofilin, predominantly dimer. Oligomerization of cofilin in cells represents one more mechanism for regulating cofilin’s actin dynamizing activity and probably underlies synaptic loss.