Reduced expression of somatostatin in GABAergic interneurons derived from induced pluripotent stem cells of patients with parkin mutations

Chizuru Iwasawa,Nobutaka Hattori,Minoru Narita,Yukari Suda,Hideyuki Okano,Naoko Kuzumaki,Reiko Kagawa,Yuko Oka

doi:10.1186/s13041-019-0426-7

Chizuru Iwasawa, Nobutaka Hattori + Show 6 more

Open Access

https://doi.org/10.1186/s13041-019-0426-7

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Abstract

Parkinson’s disease (PD) is associated with both motor and non-motor symptoms, including constipation, sensory neuropathy, depression, dementia and sleep disorder. Somatostatin (SST) is considered to be a modulator of GABAergic inhibitory transmission, and its levels are reduced in cerebrospinal fluid of PD patients. In the present study, we evaluated the changes in the expression of SST in GABAergic neurons derived from induced pluripotent stem cells (iPSCs) of PD patients. Neural cells were co-treated with the Wnt antagonist IWP-2 and Shh during neurosphere formation to induce GABA-positive forebrain interneurons. Quantitative analyses showed no significant differences, but slight decreases, in the potency of differentiation into GABAergic neurons derived from iPSCs between healthy control and patients with PARK2 mutations, who have been classified as a type of early-onset familial PD due to mutations in the parkin gene. Under this condition, the mRNA level of SST in GABAergic interneurons derived from iPSCs of PARK2-specific PD patients significantly decreased as neural maturation progressed. We also found that SST-positive GABAergic neurons were clearly reduced in GABAergic neurons derived from iPSCs of patients with PARK2 mutations. These findings suggest that the reduction in the expression level of SST in GABAergic interneurons of PD may, at least partly, lead to complex PD-induced symptoms.

Highlights

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that afflicts about 4,000,000 patients worldwide [1]
Differentiation of human Induced pluripotent stem cell (iPSC) to GABAergic neurons It has been demonstrated that the A-P identity of iPSC-derived neural progenitors can be controlled by Wnt signaling during neurosphere formation [11]
When neurotrophic factors including Brain-derived neurotrophic factor (BDNF) were used for neural maturation, Neural progenitor cell (NPC) differentiated into GABAergic neurons (Fig. 1a, b)

Summary

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that afflicts about 4,000,000 patients worldwide [1]. While PD symptoms are mainly due to the progressive degeneration of neuronal cells in the substantia nigra [2], various other types of neural cells in the central and peripheral autonomic nervous systems contribute to PD. In the central nervous system (CNS), somatostatin (SST) is highly concentrated in a large proportion of GABAergic neurons, where it acts as a co-neurotransmitter or neuromodulator to modulate excitability and neuronal responses [4, 5]. The level of SST in cerebrospinal fluid is significantly reduced in PD [7,8,9,10].

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