Quantitative Proteomic Analysis of Primitive Neural Stem Cells from LRRK2 G2019S-Associated Parkinson's Disease Patient-Derived iPSCs.

Hyuna Sim,Joo-Eun Lee,Mi-Young Son,Young-Joo Jeon,Seo-Young Lee,Ji-Hye Seo,Jung-Il Chae,Sun-Ku Chung,Areum Baek,Jumi Kim,Janghwan Kim,Minyoung Oh

doi:10.3390/life10120331

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disease, causing movement defects. The incidence of PD is constantly increasing and this disease is still incurable. Thus, understanding PD pathophysiology would be pivotal for the development of PD therapy, and various PD models have thus been already developed. Through recent advances in reprogramming techniques, a primitive neural stem cell (pNSC) derived from PD patient induced pluripotent stem cells (iPSCs) could be potentially used as a reproducible and reliable experimental system to analyze the effect of the leucine-rich repeat kinase 2 G2019S mutation (LK2GS) in neural cells. Here, we investigated the advantages of such a model system through quantitative proteomic analysis of pNSCs from normal control iPSCs and familial PD patient iPSCs harboring LK2GS. We confirmed that the expression of molecules known to be involved in PD pathogenesis, such as oxidative stress-, cell adhesion-, and cytoskeleton-related proteins, were altered in the LK2GS pNSC. In addition, we showed that down-regulation of Ku80, which was found in the proteomic analysis with LK2GS pNSCs, resulted in apoptosis induced by DNA damage response. Taken together, we suggest that pNSCs from PD iPSCs could provide a reliable and useful model system to study PD. Moreover, the highly expandable pNSC is suitable for multi-omics approaches to understand PD pathologies and discover therapeutic targets for PD.

Highlights

Parkinson’s disease (PD) is a common progressive and neurodegenerative movement disorder, with a prevalence of more than 1% beyond the age of 65 years [1]
We found that cellular apoptosis was significantly increased in leucine-rich repeat kinase 2 G2019S mutation (LK2GS)-primitive neural stem cell (pNSC) compared with that of wild type (WT)-pNSC
Several factors, including mitochondrial dysfunction, autophagy, and oxidative stress, are known to be PD is characterized by the degeneration of midbrain dopamine neurons, leading to progressive movement disorder in patients

Summary

Introduction

Parkinson’s disease (PD) is a common progressive and neurodegenerative movement disorder, with a prevalence of more than 1% beyond the age of 65 years [1]. Life 2020, 10, 331 include the age-dependent loss of dopaminergic neurons in the substantia nigra pars compacta region in the brain and the progressive spatiotemporal distribution of Lewy bodies and Lewy neurites [2]. Typical PD symptoms include motor features (postural disturbances, bradykinesia, rigidity, or tremor) and non-motor features (hyposmia, sleep disorders, or autonomic-, neuropsychiatric-, and sensory symptoms) [3]. The age at onset, progression rate, and PD severity vary, which might result from the interaction between environmental factors and genetic mutations [5]. PD incidence increases with the aging of the population, just as well as global PD prevalence. Several studies have been already reported that focus on PD diagnosis and treatment, useful PD model systems are still in demand

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