Psychosine induces the dephosphorylation of neurofilaments by deregulation of PP1 and PP2A phosphatases.
Psychosine induces the dephosphorylation of neurofilaments by deregulation of PP1 and PP2A phosphatases.
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DOI：
10.1016/j.nbd.2012.01.013
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发表时间：
2012-05
影响因子：
6.1
通讯作者：
Bongarzone, Ernesto R.
中科院分区：
文献类型：
--
作者：
Cantuti-Castelvetri, Ludovico;Zhu, Hongling;Givogri, Maria I.;Chidavaenzi, Robstein L.;Lopez-Rosas, Aurora;Bongarzone, Ernesto R.
关键词：
Krabbe病是一种由半乳糖神经酰胺酶缺乏和由此引起的半乳糖鞘脂积累引起的遗传性脱髓鞘综合征，患者表现出由大直径轴突缺乏复合的濒死轴突病的迹象。在这里，我们发现Twitcher小鼠（克拉布病的动物模型）的轴突直径在外周轴突受损，并伴有三种神经丝（NF）亚基的丰度和磷酸化的逐渐减少。这些变化与许多突变外周轴突中每横截面积NFs密度的增加以及突变组织中两种丝氨酸/苏氨酸磷酸酶（PP1和PP2A）活性的异常增加有关。同样，急性分离的突变皮质神经元也表现出异常的NFs磷酸化。克拉布病中积累的神经毒素精神碱足以诱导正常运动神经元细胞系以及急性分离的正常皮质神经元中NF亚基的异常去磷酸化。这种体外效应是由PP1和PP2A介导的，它们特异性地使NFs去磷酸化。这些结果表明，在克拉伯病的一些轴突中观察到的口径减少与NFs的异常去磷酸化有关。我们提出一种精神药物驱动的致病机制，通过解除调控的磷酸转移酶活性可能参与了这一过程。
Patients with Krabbe disease, a genetic demyelinating syndrome caused by deficiency of galactosyl-ceramidase and the resulting accumulation of galactosyl-sphingolipids, develop signs of a dying-back axonopathy compounded by a deficiency of large-caliber axons. Here, we show that axonal caliber in Twitcher mice, an animal model for Krabbe disease, is impaired in peripheral axons and is accompanied by a progressive reduction in the abundance and phosphorylation of the three neurofilament (NF) subunits. These changes correlate with an increase in the density of NFs per cross-sectional area in numerous mutant peripheral axons and abnormal increases in the activity of two serine/threonine phosphatases (PP1 and PP2A) in mutant tissue. Similarly, acutely isolated mutant cortical neurons show abnormal phosphorylation of NFs. Psychosine, the neurotoxin accumulated in Krabbe disease, was sufficient to induce abnormal dephosphorylation of NF subunits in a normal motor neuron cell line as well as in acutely isolated normal cortical neurons. This in vitro effect was mediated by PP1 and PP2A, which specifically dephosphorylated NFs. These results demonstrate that the reduced caliber observed in some axons in Krabbe disease involves abnormal dephosphorylation of NFs. We propose that a psychosine-driven pathogenic mechanism through deregulated phosphotransferase activities may be involved in this process.
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影响因子：
4.2
作者：
DEWAEGH, SM;BRADY, ST
通讯作者：
BRADY, ST
DOI：
10.1016/j.bbrc.2008.11.036
发表时间：
2009-01-16
影响因子：
3.1
作者：
Atkinson, Trevor;Whitfield, James;Chakravarthy, Balu
通讯作者：
Chakravarthy, Balu
DOI：
10.1083/jcb.149.4.943
发表时间：
2000-05-15
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kanazawa T;Nakamura S;Momoi M;Yamaji T;Takematsu H;Yano H;Sabe H;Yamamoto A;Kawasaki T;Kozutsumi Y
通讯作者：
Kozutsumi Y
影响因子：
4.4
作者：
JACOBS, JM;SCARAVILLI, F;DEARANDA, FT
通讯作者：
DEARANDA, FT
影响因子：
64.5
作者：
DEWAEGH, SM;LEE, VMY;BRADY, ST
通讯作者：
BRADY, ST