Takada Shunsuke, Mizuno Keiko, Saito Taro, Asada Akiko, Giese Karl Peter, Hisanaga Shin-Ichi
Laboratory of Molecular Neuroscience, Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, Minami-Osawa, Hachioji, Tokyo, Japan.
Centre for Cellular Basis of Behavior, Institute of Psychiatry, King's College London, 125 Coldharbour Lane, London, United Kingdom.
PLoS One. 2015 Oct 15;10(10):e0140821. doi: 10.1371/journal.pone.0140821. eCollection 2015.
p35 is an activation subunit of the cyclin-dependent kinase 5 (CDK5), which is a Ser/Thr kinase that is expressed predominantly in neurons. Disruption of the CDK5 or p35 (CDK5R1) genes induces abnormal neuronal layering in various regions of the mouse brain via impaired neuronal migration, which may be relevant for mental retardation in humans. Accordingly, mutations in the p35 gene were reported in patients with nonsyndromic mental retardation; however, their effect on the biochemical function of p35 has not been examined. Here, we studied the biochemical effect of mutant p35 on its known properties, i.e., stability, CDK5 activation, and cellular localization, using heterologous expression in cultured cells. We also examined the effect of the mutations on axon elongation in cultured primary neurons and migration of newborn neurons in embryonic brains. However, we did not detect any significant differences in the effects of the mutant forms of p35 compared with wild-type p35. Therefore, we conclude that these p35 mutations are unlikely to cause mental retardation.
p35是细胞周期蛋白依赖性激酶5（CDK5）的一个激活亚基，CDK5是一种丝氨酸/苏氨酸激酶，主要在神经元中表达。CDK5或p35（CDK5R1）基因的破坏会通过受损的神经元迁移在小鼠大脑的各个区域诱导异常的神经元分层，这可能与人类的智力迟钝有关。因此，在非综合征性智力迟钝患者中报道了p35基因的突变；然而，它们对p35生化功能的影响尚未得到研究。在这里，我们利用培养细胞中的异源表达研究了突变型p35对其已知特性，即稳定性、CDK5激活和细胞定位的生化影响。我们还研究了这些突变对培养的原代神经元轴突伸长和胚胎大脑中新生神经元迁移的影响。然而，与野生型p35相比，我们没有检测到p35突变形式的影响有任何显著差异。因此，我们得出结论，这些p35突变不太可能导致智力迟钝。
