Cerebellar Neurodegeneration and Neuronal Circuit Remodeling in Golgi pH Regulator-Deficient Mice
Cerebellar Neurodegeneration and Neuronal Circuit Remodeling in Golgi pH Regulator-Deficient Mice
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DOI：
10.1523/eneuro.0427-18.2019
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发表时间：
2019-05
期刊：
影响因子：
3.4
通讯作者：
Yu-Shin Sou;S. Kakuta;Y. Kamikubo;K. Niisato;Takashi Sakurai;L. Parajuli;I. Tanida;Hiromitsu Saito;Noboru Suzuki;K. Sakimura;Y. Maeda;T. Kinoshita;Y. Uchiyama;M. Koike
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文献类型：
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作者：
Yu-Shin Sou;S. Kakuta;Y. Kamikubo;K. Niisato;Takashi Sakurai;L. Parajuli;I. Tanida;Hiromitsu Saito;Noboru Suzuki;K. Sakimura;Y. Maeda;T. Kinoshita;Y. Uchiyama;M. Koike
摘要高尔基体在蛋白质的翻译后修饰和转运过程中起着不可或缺的作用。虽然已经确定高尔基体需要酸性的管腔pH才能达到最佳活动，但由于高尔基体pH的扰动而导致的神经元回路水平的形态和功能异常尚不完全清楚。此外，高尔基体的形态改变与几种神经退行性疾病有关，包括帕金森氏病、阿尔茨海默病和肌萎缩侧索硬化症。在这里，我们使用解剖学和电生理学的方法来表征高尔基体pH调节器(GPHR)条件性基因敲除小鼠神经元回路的形态和功能异常。突变小鼠的浦肯野细胞(PC)表现出高尔基体的囊泡和碎裂，随后出现轴突变性和进行性细胞丢失。形态分析提供了PC胞体周围篮状细胞(BC)终末断裂的证据，电生理记录显示大幅值反应选择性丢失，提示BC终末解体。此外，突变的PC的神经支配发生了改变，以至于在成熟的小脑中，爬升纤维(CF)终末异常地突触到突变的PC的体刺上。这些综合的结果描述了高尔基体的管腔酸化在维持适当的神经元形态和神经元回路方面的重要作用。
Abstract The Golgi apparatus plays an indispensable role in posttranslational modification and transport of proteins to their target destinations. Although it is well established that the Golgi apparatus requires an acidic luminal pH for optimal activity, morphological and functional abnormalities at the neuronal circuit level because of perturbations in Golgi pH are not fully understood. In addition, morphological alteration of the Golgi apparatus is associated with several neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. Here, we used anatomical and electrophysiological approaches to characterize morphological and functional abnormalities of neuronal circuits in Golgi pH regulator (GPHR) conditional knock-out mice. Purkinje cells (PCs) from the mutant mice exhibited vesiculation and fragmentation of the Golgi apparatus, followed by axonal degeneration and progressive cell loss. Morphological analysis provided evidence for the disruption of basket cell (BC) terminals around PC soma, and electrophysiological recordings showed selective loss of large amplitude responses, suggesting BC terminal disassembly. In addition, the innervation of mutant PCs was altered such that climbing fiber (CF) terminals abnormally synapsed on the somatic spines of mutant PCs in the mature cerebellum. The combined results describe an essential role for luminal acidification of the Golgi apparatus in maintaining proper neuronal morphology and neuronal circuitry.