scholarly journals Highly enriched hiPSC-derived midbrain dopaminergic neurons robustly models Parkinson’s disease

2020 ◽  
Author(s):  
Gurvir S Virdi ◽  
Minee L Choi ◽  
Zhi Yao ◽  
James R Evans ◽  
Dilan Athauda ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Single Cell ◽  
Molecular Mechanisms ◽  
Calcium Signalling ◽  
Patient Specific ◽  
Midbrain Dopaminergic Neurons ◽  
Dopamine Transport ◽  
Induced Pluripotent ◽  
Key Aspects

AbstractThe development of human induced pluripotent stem cells (hiPSC) has greatly aided our ability to model neurodegenerative diseases. However, generation of midbrain dopaminergic (mDA) neurons is a major challenge and protocols are variable. Here, we developed a method to differentiate hiPSCs into enriched populations (>80%) of mDA neurons using only small molecules. We confirmed the identity of the mDA neurons using single-cell RNA-sequencing and detection of classical markers. Single-cell live imaging demonstrated neuronal calcium signalling and functional dopamine transport. Electrophysiology measures highlighted the ability to form synapses and networks in culture. Patient-specific hiPSC lines differentiated to produce functional mDA neurons that exhibit the hallmarks of synucleinopathy including: aggregate formation, oxidative stress as well as mitochondrial dysfunction and impaired lysosomal dynamics. In summary, we establish a robust differentiation paradigm to generate enriched mDA neurons from hiPSCs, which can be used to faithfully model key aspects of Parkinson’s disease (PD), providing the potential to further elucidate molecular mechanisms contributing to disease development.

scholarly journals Modeling Parkinson’s Disease Using Induced Pluripotent Stem Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Xinchao Hu ◽  
Chengyuan Mao ◽  
Liyuan Fan ◽  
Haiyang Luo ◽  
Zhengwei Hu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Molecular Mechanisms ◽  
Cellular Level ◽  
Patient Specific ◽  
Ubiquitin Protein Ligase ◽  
Induced Pluripotent

Parkinson’s disease (PD) is the second most common neurodegenerative disease. The molecular mechanisms of PD at the cellular level involve oxidative stress, mitochondrial dysfunction, autophagy, axonal transport, and neuroinflammation. Induced pluripotent stem cells (iPSCs) with patient-specific genetic background are capable of directed differentiation into dopaminergic neurons. Cell models based on iPSCs are powerful tools for studying the molecular mechanisms of PD. The iPSCs used for PD studies were mainly from patients carrying mutations in synuclein alpha (SNCA), leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1), parkin RBR E3 ubiquitin protein ligase (PARK2), cytoplasmic protein sorting 35 (VPS35), and variants in glucosidase beta acid (GBA). In this review, we summarized the advances in molecular mechanisms of Parkinson’s disease using iPSC models.

scholarly journals Modeling Parkinson’s Disease and Atypical Parkinsonian Syndromes Using Induced Pluripotent Stem Cells

2018 ◽  
Vol 19 (12) ◽  
pp. 3870 ◽  
Author(s):  
Takayasu Mishima ◽  
Shinsuke Fujioka ◽  
Jiro Fukae ◽  
Junichi Yuasa-Kawada ◽  
Yoshio Tsuboi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Induced Pluripotent Stem Cell ◽  
Chromosome 17 ◽  
Patient Specific ◽  
Muscle Rigidity ◽  
Parkinsonian Syndromes ◽  
Induced Pluripotent ◽  
Key Aspects

Parkinson’s disease (PD) and atypical parkinsonian syndromes are age-dependent multifactorial neurodegenerative diseases, which are clinically characterized by bradykinesia, tremor, muscle rigidity and postural instability. Although these diseases share several common clinical phenotypes, their pathophysiological aspects vary among the disease categories. Extensive animal-based approaches, as well as postmortem studies, have provided important insights into the disease mechanisms and potential therapeutic targets. However, the exact pathological mechanisms triggering such diseases still remain elusive. Furthermore, the effects of drugs observed in animal models are not always reproduced in human clinical trials. By using induced pluripotent stem cell (iPSC) technology, it has become possible to establish patient-specific iPSCs from their somatic cells and to effectively differentiate these iPSCs into different types of neurons, reproducing some key aspects of the disease phenotypes in vitro. In this review, we summarize recent findings from iPSC-based modeling of PD and several atypical parkinsonian syndromes including multiple system atrophy, frontotemporal dementia and parkinsonism linked to chromosome 17 and Perry syndrome. Furthermore, we discuss future challenges and prospects for modeling and understanding PD and atypical parkinsonian syndromes.

scholarly journals Modeling the pathophysiology of Parkinson’s disease in patient-specific neurons

2020 ◽  
pp. 153537022096178
Author(s):  
Jian Feng
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Stem Cell ◽  
Basal Ganglia ◽  
Pluripotent Stem Cells ◽  
Patient Specific ◽  
Mechanistic Studies ◽  
Induced Pluripotent ◽  
Further Development

The 30 trillion cells that self-assemble into a human being originate from the pluripotent stem cells in the inner cell mass of a human blastocyst. The discovery of induced pluripotent stem cells (iPSCs) makes it possible to approximate various aspects of this natural developmental process artificially by generating materials that can be used in invasive mechanistic studies of virtually all human conditions. In Parkinson’s disease, instructions computed by the basal ganglia to control voluntary motor functions break down, leading to widespread rhythmic bursting activities in the basal ganglia and beyond. It is thought that these oscillatory neuronal activities, which disrupt aperiodic neurotransmission in a normal brain, may reduce information content in the instructions for motor control. Using midbrain neuronal cultures differentiated from iPSCs of Parkinson’s disease patients with parkin mutations, we find that parkin mutations cause oscillatory neuronal activities when dopamine D1-class receptors are activated. This system makes it possible to study the molecular basis of rhythmic bursting activities in Parkinson’s disease. Further development of stem cell models of Parkinson’s disease will enable better approximation of the situation in the brain of Parkinson’s disease patients. In this review, I will discuss what has been found in the past about the pathophysiology of motor dysfunction in Parkinson’s disease, especially oscillatory neuronal activities and how stem cell technologies may transform our abilities to understand the pathophysiology of Parkinson’s disease. Impact statement Research on the pathophysiology of Parkinson’s disease (PD) has generated effective therapies such as deep brain stimulation. A better understanding of PD pathophysiology calls for patient-specific materials amenable for invasive mechanistic studies. In this minireview, I discuss our recent work on oscillatory neuronal activities in midbrain neurons differentiated from induced pluripotent stem cells (iPSCs) of PD patients with parkin mutations. These patient-specific neurons enable a variety of studies previously not feasible in the human system. Further development in stem cell technologies may generate more realistic models for us to decipher PD pathophysiology. These new developments will transform research and development in Parkinson’s disease.

scholarly journals Dissecting the non-neuronal cell contribution to Parkinson’s disease pathogenesis using induced pluripotent stem cells

2020 ◽  
Author(s):  
Meritxell Pons-Espinal ◽  
Lucas Blasco-Agell ◽  
Antonella Consiglio
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Glial Cells ◽  
Cell Function ◽  
Neuronal Cell ◽  
Induced Pluripotent Stem Cell ◽  
Substantia Nigra Pars Compacta ◽  
Patient Specific ◽  
Human Patient ◽  
Induced Pluripotent

AbstractParkinson’s disease (PD) is an incurable age-linked neurodegenerative disease with characteristic movement impairments that are caused by the progressive loss of dopamine-containing neurons (DAn) within the substantia nigra pars compacta. It has been suggested that misfolded protein aggregates together with neuroinflammation and glial reactivity, may impact nerve cell function, leading to neurodegeneration and diseases, such as PD. However, not many studies have been able to examine the role of human glial cells in the pathogenesis of PD. With the advent of induced pluripotent stem cell (iPSC) technology, it is now possible to reprogram human somatic cells to pluripotency and to generate viable human patient-specific DA neurons and glial cells, providing a tremendous opportunity for dissecting cellular and molecular pathological mechanisms occurring at early stages of PD. This reviews will report on recent work using human iPSC and 3D brain organoid models showing that iPSC technology can be used to recapitulate PD-relevant disease-associated phenotypes, including protein aggregation, cell death or loss of neurite complexity and deficient autophagic vacuoles clearance and focus on the recent co-culture systems that are revealing new insights into the complex interactions that occur between different brain cell types during neurodegeneration. Consequently, such advances are the key to improve our understanding of PD pathology and generate potential targets for new therapies aimed at curing PD patients.

scholarly journals Treatment of Parkinson’s Disease through Personalized Medicine and Induced Pluripotent Stem Cells

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 26 ◽  
Author(s):  
Theo Stoddard-Bennett ◽  
Renee Reijo Pera
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Personalized Medicine ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Substantia Nigra Pars Compacta ◽  
Model Organisms ◽  
Patient Specific ◽  
Induced Pluripotent

Parkinson’s Disease (PD) is an intractable disease resulting in localized neurodegeneration of dopaminergic neurons of the substantia nigra pars compacta. Many current therapies of PD can only address the symptoms and not the underlying neurodegeneration of PD. To better understand the pathophysiological condition, researchers continue to seek models that mirror PD’s phenotypic manifestations as closely as possible. Recent advances in the field of cellular reprogramming and personalized medicine now allow for previously unattainable cell therapies and patient-specific modeling of PD using induced pluripotent stem cells (iPSCs). iPSCs can be selectively differentiated into a dopaminergic neuron fate naturally susceptible to neurodegeneration. In iPSC models, unlike other artificially-induced models, endogenous cellular machinery and transcriptional feedback are preserved, a fundamental step in accurately modeling this genetically complex disease. In addition to accurately modeling PD, iPSC lines can also be established with specific genetic risk factors to assess genetic sub-populations’ differing response to treatment. iPS cell lines can then be genetically corrected and subsequently transplanted back into the patient in hopes of re-establishing function. Current techniques focus on iPSCs because they are patient-specific, thereby reducing the risk of immune rejection. The year 2018 marked history as the year that the first human trial for PD iPSC transplantation began in Japan. This form of cell therapy has shown promising results in other model organisms and is currently one of our best options in slowing or even halting the progression of PD. Here, we examine the genetic contributions that have reshaped our understanding of PD, as well as the advantages and applications of iPSCs for modeling disease and personalized therapies.

scholarly journals Current Approaches and Molecular Mechanisms for Directly Reprogramming Fibroblasts Into Neurons and Dopamine Neurons

2021 ◽  
Vol 13 ◽  
Author(s):  
Fabin Han ◽  
Yanming Liu ◽  
Jin Huang ◽  
Xiaoping Zhang ◽  
Chuanfei Wei
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Immune System ◽  
Neural Stem Cells ◽  
Molecular Mechanisms ◽  
Embryonic Stem ◽  
Dopamine Neurons ◽  
Patient Specific ◽  
Direct Reprogramming

Parkinson’s disease is mainly caused by specific degeneration of dopaminergic neurons (DA neurons) in the substantia nigra of the middle brain. Over the past two decades, transplantation of neural stem cells (NSCs) from fetal brain-derived neural stem cells (fNSCs), human embryonic stem cells (hESCs), and induced pluripotent stem cells (iPSCs) has been shown to improve the symptoms of motor dysfunction in Parkinson’s disease (PD) animal models and PD patients significantly. However, there are ethical concerns with fNSCs and hESCs and there is an issue of rejection by the immune system, and the iPSCs may involve tumorigenicity caused by the integration of the transgenes. Recent studies have shown that somatic fibroblasts can be directly reprogrammed to NSCs, neurons, and specific dopamine neurons. Directly induced neurons (iN) or induced DA neurons (iDANs) from somatic fibroblasts have several advantages over iPSC cells. The neurons produced by direct transdifferentiation do not pass through a pluripotent state. Therefore, direct reprogramming can generate patient-specific cells, and it can overcome the safety problems of rejection by the immune system and teratoma formation related to hESCs and iPSCs. However, there are some critical issues such as the low efficiency of direct reprogramming, biological functions, and risks from the directly converted neurons, which hinder their clinical applications. Here, the recent progress in methods, mechanisms, and future challenges of directly reprogramming somatic fibroblasts into neurons or dopamine neurons were summarized to speed up the clinical translation of these directly converted neural cells to treat PD and other neurodegenerative diseases.

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