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eNeuro. 2019 May 29;6(3). pii: ENEURO.0427-18.2019. doi: 10.1523/ENEURO.0427-18.2019. Print 2019 May/Jun.

Cerebellar Neurodegeneration and Neuronal Circuit Remodeling in Golgi pH Regulator-Deficient Mice.

Author information

1
Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Bunkyo, Tokyo 113-8421, Japan ysodaka@juntendo.ac.jp mkoike@juntendo.ac.jp.
2
Laboratory of Morphology and Image Analysis, Research Support Center, Juntendo University Graduate School of Medicine, Bunkyo, Tokyo 113-8421, Japan.
3
Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Bunkyo, Tokyo 113-8421, Japan.
4
Department of Pharmacology, Juntendo University Graduate School of Medicine, Bunkyo, Tokyo 113-8421, Japan.
5
Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Bunkyo, Tokyo 113-8421, Japan.
6
Functional Genomics Institute, Life Science Research Center, Mie University, Tsu, Mie 514-8507, Japan.
7
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
8
Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
9
Advanced Research Institute for Health Science, Juntendo University, Bunkyo, Tokyo 113-8421, Japan.

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.

KEYWORDS:

Golgi apparatus; Golgi fragmentation; Golgi pH regulator; Purkinje cell; cerebellar circuit; neurodegeneration

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