Research on the fundamental molecules in relation to controlling brain aging : From neuronal cytoskeleton regulation to neuronal longevity control

虽然我之前建立了N-Shc基因缺陷小鼠，即所谓的KO小鼠，但现在我们制造了N-Shc和GRIT/RICS双重KO小鼠。为了了解N-Shc调节肌动蛋白动力学的分子机制，我们研究了神经元突触上肌动蛋白锚定分子Hmer/Cupidin的作用。我们还利用NRSF/REST分析了BDNF启动子的转录调控机制。众所周知，在老年人的大脑中，各种功能，特别是海马体和大脑中的功能确实会下降，但对小脑功能知之甚少。因此，我们询问了小脑突触LTP在衰老过程中是否发生变化，发现它确实随着年龄的增长而下降。我们进一步发现LTP的减少受到氧化应激的强烈影响。由于平行纤维-浦肯野细胞突触的LTP依赖于一氧化氮(NO)，我们假设并最终证明了这种依赖NO的LTP在衰老过程中受到氧化应激的损害。我们还分析了HDAC6和SIRT2在神经元蛋白质聚集周转中的作用，发现HDAC6刺激多聚谷氨酰胺调节的蛋白质在神经细胞中聚集，这可能与年龄相关神经退行性疾病的研究有关。最后，我们成立了亚洲老龄化研究联盟。

While I previously established N-Shc gene deficient mouse, the so-called KO mouse, we now made N-Shc and Grit/RICS double KO mouse. In norder to understand molecular mechanisms of actin dynamics regulation via N-Shc, we examined the role of Homer/Cupidin, an anchoring molecule to actins at neuronal synapses. We also analyzed the transcriptional regulatory mechanisms of BDNF promoter by NRSF/REST. In aged brains, it has been well known that various functions, particularly in hippocampus and cerebram, do decrease, but little is known about the cerebellar function. We, therefore, asked whether synaptic LTP in cerebellum changes or not in aging, and found that it indeed declined with age. We further found that the reduction of LTP is strongly affected by oxidative stress. Since the LTP at parallel fiber-Purkinje cell synapse depend on NO (nitric oxide), we assumed and finally demonstrated that this NO-dependent LTP is impaired by oxidative stress during aging. We also analyzed the effects of HDAC6 and SIRT2 in the protein aggregate turnover in neurons, and found that HDAC6 stimulated poly glutamin-mdiated protain aggregation in neuronal cells, which may be relevant to the studies of age-related neurodegenerative diseases. Finally, we established Asian research consortium on aging.