Modeling Parkinson’s Disease Using Induced Pluripotent Stem Cells

Hu, Xingwang; Mao, Chengyuan; Fan, Liyuan; Luo, Hui; Hu, Z. W.; Zhang, Shuo; Yang, Zhihua; Zheng, Huimin; Sun, Huifang; Fan, Yu; Yang, Jing; Shi, Changhe; Xu, Yuming

doi:10.1155/2020/1061470

Cited by 24 publications

(24 citation statements)

References 165 publications

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“…A number of recent reviews have focused on the advantage of using iPSCs in PD modelling which have contributed extensively to our knowledge [ 23 , 24 ]. However, a more comprehensive and detailed study of iPSC modelling and their related phenotypes to a specific genomic background and their ultimate relation to human pathology is lacking.…”

Section: Introductionmentioning

confidence: 99%

Modelling Parkinson’s Disease: iPSCs towards Better Understanding of Human Pathology

et al. 2021

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Parkinson’s Disease (PD) is a chronic neurodegenerative disorder characterized by motor and non-motor symptoms, among which are bradykinesia, rigidity, tremor as well as mental symptoms such as dementia. The underlying cause of Parkinson disease is degeneration of dopaminergic neurons. It has been challenging to develop an efficient animal model to accurately represent the complex phenotypes found with PD. However, it has become possible to recapitulate the myriad of phenotypes underlying the PD pathology by using human induced pluripotent stem cell (iPSC) technology. Patient-specific iPSC-derived dopaminergic neurons are available and present an opportunity to study many aspects of the PD phenotypes in a dish. In this review, we report the available data on iPSC-derived neurons derived from PD patients with identified gene mutations. Specifically, we will report on the key phenotypes of the generated iPSC-derived neurons from PD patients with different genetic background. Furthermore, we discuss the relationship these cellular phenotypes have to PD pathology and future challenges and prospects for iPSC modelling and understanding of the pathogenesis of PD.

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Section: Introductionmentioning

confidence: 99%

Modelling Parkinson’s Disease: iPSCs towards Better Understanding of Human Pathology

et al. 2021

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“…Alternatively, genome editing technologies (e.g., CRISPR/Cas) can be applied to introduce specific mutations in iPSCs or to generate isogenic control lines [ 76 ]. Experiments on iPSCs expressing different pathogenic mutations in the PD gene, leucine-rich repeat kinase 2 ( LRRK2 ), e.g., p.G2019S, showed disrupted mechanisms including aggregation of α-synuclein, mitochondrial transport, and lysosomal autophagy [ 77 ]. These iPSCs are also beneficial to measure the resulting cellular phenotypes to allow the identification of new therapeutics [ 78 ].…”

Section: Relevance Of Understanding the Role Of Rare Variantsmentioning

confidence: 99%

Emerging genetic complexity and rare genetic variants in neurodegenerative brain diseases

et al. 2021

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Knowledge of the molecular etiology of neurodegenerative brain diseases (NBD) has substantially increased over the past three decades. Early genetic studies of NBD families identified rare and highly penetrant deleterious mutations in causal genes that segregate with disease. Large genome-wide association studies uncovered common genetic variants that influenced disease risk. Major developments in next-generation sequencing (NGS) technologies accelerated gene discoveries at an unprecedented rate and revealed novel pathways underlying NBD pathogenesis. NGS technology exposed large numbers of rare genetic variants of uncertain significance (VUS) in coding regions, highlighting the genetic complexity of NBD. Since experimental studies of these coding rare VUS are largely lacking, the potential contributions of VUS to NBD etiology remain unknown. In this review, we summarize novel findings in NBD genetic etiology driven by NGS and the impact of rare VUS on NBD etiology. We consider different mechanisms by which rare VUS can act and influence NBD pathophysiology and discuss why a better understanding of rare VUS is instrumental for deriving novel insights into the molecular complexity and heterogeneity of NBD. New knowledge might open avenues for effective personalized therapies.

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“…S-181 efficiency was confirmed in vivo, as its administration to mice was shown to decrease the brain alpha-synculein level [ 186 ]. Human DA neurons generated from iPS cells were shown to be a valuable model for studying the role of oxidative stress in the development of PD and assessment of potential antioxidants [ 187 ]. For instance, neuroprotective effects of a small molecule antioxidant NC001-8 were demonstrated using iPS cell-derived DA neurons that were challenged with hydrogen peroxide [ 188 ].…”

Section: The Use Of Ips Cell-derived Neurons In Drug Development Amentioning

confidence: 99%

Current State-of-the-Art and Unresolved Problems in Using Human Induced Pluripotent Stem Cell-Derived Dopamine Neurons for Parkinson’s Disease Drug Development

Antonov

Новосадова

2021

IJMS

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Human induced pluripotent stem (iPS) cells have the potential to give rise to a new era in Parkinson’s disease (PD) research. As a unique source of midbrain dopaminergic (DA) neurons, iPS cells provide unparalleled capabilities for investigating the pathogenesis of PD, the development of novel anti-parkinsonian drugs, and personalized therapy design. Significant progress in developmental biology of midbrain DA neurons laid the foundation for their efficient derivation from iPS cells. The introduction of 3D culture methods to mimic the brain microenvironment further expanded the vast opportunities of iPS cell-based research of the neurodegenerative diseases. However, while the benefits for basic and applied studies provided by iPS cells receive widespread coverage in the current literature, the drawbacks of this model in its current state, and in particular, the aspects of differentiation protocols requiring further refinement are commonly overlooked. This review summarizes the recent data on general and subtype-specific features of midbrain DA neurons and their development. Here, we review the current protocols for derivation of DA neurons from human iPS cells and outline their general weak spots. The associated gaps in the contemporary knowledge are considered and the possible directions for future research that may assist in improving the differentiation conditions and increase the efficiency of using iPS cell-derived neurons for PD drug development are discussed.

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Modeling Parkinson’s Disease Using Induced Pluripotent Stem Cells

Cited by 24 publications

References 165 publications

Modelling Parkinson’s Disease: iPSCs towards Better Understanding of Human Pathology

Modelling Parkinson’s Disease: iPSCs towards Better Understanding of Human Pathology

Emerging genetic complexity and rare genetic variants in neurodegenerative brain diseases

Current State-of-the-Art and Unresolved Problems in Using Human Induced Pluripotent Stem Cell-Derived Dopamine Neurons for Parkinson’s Disease Drug Development

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