Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139.
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
Proc Natl Acad Sci U S A. 2023 Apr 18;120(16):e2217864120. doi: 10.1073/pnas.2217864120. Epub 2023 Apr 12.
Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This deleterious effect is mediated by pathological cleavage of the Cdk5 activator p35 into the truncated product p25, leading to prolonged Cdk5 activation and altered substrate specificity. Elevated p25 levels have been reported in humans and rodents with neurodegeneration, and the benefit of genetically blocking p25 production has been demonstrated previously in rodent and human neurodegenerative models. Here, we report a 12-amino-acid-long peptide fragment derived from Cdk5 (Cdk5i) that is considerably smaller than existing peptide inhibitors of Cdk5 (P5 and CIP) but shows high binding affinity toward the Cdk5/p25 complex, disrupts the interaction of Cdk5 with p25, and lowers Cdk5/p25 kinase activity. When tagged with a fluorophore (FITC) and the cell-penetrating transactivator of transcription (TAT) sequence, the Cdk5i-FT peptide exhibits cell- and brain-penetrant properties and confers protection against neurodegenerative phenotypes associated with Cdk5 hyperactivity in cell and mouse models of neurodegeneration, highlighting Cdk5i's therapeutic potential.
细胞周期蛋白依赖性激酶（Cdk5）的异常活性与各种神经退行性疾病有关。这种有害作用是通过 Cdk5 激活剂 p35 的病理性切割为截短产物 p25 来介导的，导致 Cdk5 的持续激活和改变的底物特异性。在神经退行性变的人类和啮齿动物中已经报道了升高的 p25 水平，并且以前已经在啮齿动物和人类神经退行性模型中证明了遗传阻断 p25 产生的益处。在这里，我们报告了一种源自 Cdk5 的 12 个氨基酸长的肽片段（Cdk5i），它比现有的 Cdk5 肽抑制剂（P5 和 CIP）小得多，但对 Cdk5/p25 复合物具有高结合亲和力，破坏 Cdk5 与 p25 的相互作用，并降低 Cdk5/p25 激酶活性。当与荧光团（FITC）和穿透细胞的转录激活物（TAT）序列缀合时，Cdk5i-FT 肽表现出细胞和脑穿透特性，并赋予针对细胞和小鼠神经退行性模型中与 Cdk5 过度活性相关的神经退行性表型的保护作用，突出了 Cdk5i 的治疗潜力。
