Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):14330-5. doi: 10.1073/pnas.1105172108. Epub 2011 Aug 15.
The activity of Cdk5 and its regulatory subunit p35 is thought to be important in both normal brain function and neurodegenerative disease pathogenesis. Increased Cdk5 activity, via proteolytic cleavage of p35 to a p25 fragment by the calcium-activated protease calpain or by phosphorylation at Cdk5(Tyr15), can contribute to neurotoxicity. Nonetheless, our knowledge of regulation of Cdk5 activity in disease states is still emerging. Here we demonstrate that Cdk5 is activated by S-nitrosylation or reaction of nitric oxide (NO)-related species with the thiol groups of cysteine residues 83 and 157, to form SNO-Cdk5. We then show that S-nitrosylation of Cdk5 contributes to amyloid-β (Aβ) peptide-induced dendritic spine loss. Furthermore, we observed significant levels of SNO-Cdk5 in postmortem Alzheimer's disease (AD) but not in normal human brains. These findings suggest that S-nitrosylation of Cdk5 is an aberrant regulatory mechanism of enzyme activity that may contribute to the pathogenesis of AD.
Cdk5 及其调节亚基 p35 的活性被认为在正常大脑功能和神经退行性疾病发病机制中都很重要。通过钙激活蛋白酶钙蛋白酶将 p35 蛋白水解切割为 p25 片段，或通过 Cdk5(Tyr15)的磷酸化，增加 Cdk5 的活性可导致神经毒性。尽管如此，我们对疾病状态下 Cdk5 活性的调节的了解仍在不断发展。在这里，我们证明 Cdk5 通过 S-亚硝基化或一氧化氮（NO）相关物质与半胱氨酸残基 83 和 157 的巯基反应被激活，形成 SNO-Cdk5。然后，我们表明 Cdk5 的 S-亚硝基化导致淀粉样β（Aβ）肽诱导的树突棘丢失。此外，我们在阿尔茨海默病（AD）的死后脑组织中观察到明显水平的 SNO-Cdk5，但在正常的人脑组织中则没有。这些发现表明，Cdk5 的 S-亚硝基化是一种酶活性的异常调节机制，可能导致 AD 的发病机制。
