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

Overview

Journal eNeuro

Specialty Neurology

Date 2019 May 24

PMID 31118204

Citations 6

Authors

Yu-Shin Sou

Soichiro Kakuta

Yuji Kamikubo

Kazue Niisato

Takashi Sakurai

Laxmi Kumar Parajuli

Isei Tanida

Hiromitsu Saito

Noboru Suzuki

Kenji Sakimura

Yusuke Maeda

Taroh Kinoshita

Yasuo Uchiyama

Masato Koike

Affiliations

Soon will be listed here.

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.

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