Koob Andrew O, Shaked Gideon M, Bender Andreas, Bisquertt Alejandro, Rockenstein Edward, Masliah Eliezer
Departments of Neurosciences, 9500 Gilman Drive, University of California, San Diego, La Jolla, CA 92093-0624, United States; Departments of Psychiatry, 9500 Gilman Drive, University of California, San Diego, La Jolla, CA 92093-0624, United States.
Departments of Neurosciences, 9500 Gilman Drive, University of California, San Diego, La Jolla, CA 92093-0624, United States.
Brain Res. 2014 Dec 3;1591:102-10. doi: 10.1016/j.brainres.2014.10.013. Epub 2014 Oct 19.
Neurogranin is a calmodulin binding protein that has been implicated in learning and memory, long-term potentiation and synaptic plasticity. Neurons expressing neurogranin in the cortex degenerate in late stages of Parkinson's disease with widespread α-synuclein pathology. While analyzing neurogranin gene expression levels through rtPCR in brains of mouse models overexpressing human α-synuclein, we found levels were elevated 2.5 times when compared to nontransgenic animals. Immunohistochemistry in the cortex revealed colocalization between α-synuclein and neurogranin in mouse transgenics when compared to control mice. Coimmunoprecipitation studies in the superior temporal cortex in humans confirmed interaction between α-synuclein and neurogranin, and decreased interaction between α-synuclein and neurogranin was noticed in patients diagnosed with Parkinson's disease when compared to normal control brains. Additionally, phosphorylated neurogranin levels were also decreased in the human superior temporal cortex in patients diagnosed with Parkinson's disease and patients diagnosed with dementia with Lewy bodies. Here, we show for the first time that neurogranin binds to α-synuclein in the human cortex, and this interaction decreases in Parkinson's disease along with the phosphorylation of neurogranin, a molecular process thought to be involved in learning and memory.
神经颗粒素是一种钙调蛋白结合蛋白，与学习和记忆、长时程增强及突触可塑性有关。在帕金森病晚期，随着广泛的α-突触核蛋白病变，皮质中表达神经颗粒素的神经元会发生退化。在对过表达人α-突触核蛋白的小鼠模型脑内通过逆转录聚合酶链反应（rtPCR）分析神经颗粒素基因表达水平时，我们发现与非转基因动物相比，其水平升高了2.5倍。与对照小鼠相比，对小鼠转基因体皮质进行的免疫组织化学显示α-突触核蛋白与神经颗粒素共定位。对人类颞上叶皮质进行的免疫共沉淀研究证实了α-突触核蛋白与神经颗粒素之间存在相互作用，并且与正常对照脑相比，在被诊断为帕金森病的患者中发现α-突触核蛋白与神经颗粒素之间的相互作用减弱。此外，在被诊断为帕金森病的患者和被诊断为路易体痴呆的患者的人类颞上叶皮质中，磷酸化神经颗粒素水平也降低。在此，我们首次表明神经颗粒素在人类皮质中与α-突触核蛋白结合，并且在帕金森病中这种相互作用会减弱，同时神经颗粒素的磷酸化也会减弱，而这一分子过程被认为与学习和记忆有关。
