Modeling G2019S-LRRK2 Sporadic Parkinson's Disease in 3D Midbrain Organoids

Kim, Hongwon; Park, Hyeok Ju; Choi, Hwan Geun; Chang, Yu‐Jung; Park, Hanseul; Shin, Jaein; Kim, Junyeop; Lengner, Christopher J.; Lee, Yong Kyu; Kim, Jong-Pil

doi:10.1016/j.stemcr.2019.01.020

Cited by 244 publications

(246 citation statements)

References 43 publications

(48 reference statements)

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“…Here, TXNIP gene expression (which is a major regulator of cellular redox signaling protecting cells from oxidative stress) was upregulated in midbrain organoids carrying the mutation compared to isogenic controls. These results suggested a direct relationship between α-synuclein (a hallmark of PD pathogenesis) and TXNIP [39], offering a new drug target for the treatment of sporadic PD.…”

Section: Human Induced Pluripotent Stem Cell (Hipsc)-derived Region-smentioning

confidence: 85%

Unprecedented Potential for Neural Drug Discovery Based on Self-Organizing hiPSC Platforms

et al. 2020

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Human induced pluripotent stem cells (hiPSCs) have transformed conventional drug discovery pathways in recent years. In particular, recent advances in hiPSC biology, including organoid technologies, have highlighted a new potential for neural drug discovery with clear advantages over the use of primary tissues. This is important considering the financial and social burden of neurological health care worldwide, directly impacting the life expectancy of many populations. Patient-derived iPSCs-neurons are invaluable tools for novel drug-screening and precision medicine approaches directly aimed at reducing the burden imposed by the increasing prevalence of neurological disorders in an aging population. 3-Dimensional self-assembled or so-called ‘organoid’ hiPSCs cultures offer key advantages over traditional 2D ones and may well be gamechangers in the drug-discovery quest for neurological disorders in the coming years.

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Section: Human Induced Pluripotent Stem Cell (Hipsc)-derived Region-smentioning

confidence: 85%

Unprecedented Potential for Neural Drug Discovery Based on Self-Organizing hiPSC Platforms

et al. 2020

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“…For the first time was the concept of whole-brain organoid formation within the same 3D platform published by Lancaster and Knoblich [43]. Within the past years, several brain organoid models of various neural diseases, such as Alzheimer's disease [44,45] Parkinson's disease [46,47], neuropsychiatric disease [48], Miller-Dieker syndrome [49], sever microcephaly [50] and also HD [51] have been generated.…”

Section: Ipsc-derived Brain Organoid Modelsmentioning

confidence: 99%

Recent Overview of the Use of iPSCs Huntington’s Disease Modeling and Therapy

Csöbönyeiová

Polák

Danišovič

2020

IJMS

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Huntington’s disease (HD) is an inherited, autosomal dominant, degenerative disease characterized by involuntary movements, cognitive decline, and behavioral impairment ending in death. HD is caused by an expansion in the number of CAG repeats in the huntingtin gene on chromosome 4. To date, no effective therapy for preventing the onset or progression of the disease has been found, and many symptoms do not respond to pharmacologic treatment. However, recent results of pre-clinical trials suggest a beneficial effect of stem-cell-based therapy. Induced pluripotent stem cells (iPSCs) represent an unlimited cell source and are the most suitable among the various types of autologous stem cells due to their patient specificity and ability to differentiate into a variety of cell types both in vitro and in vivo. Furthermore, the cultivation of iPSC-derived neural cells offers the possibility of studying the etiopathology of neurodegenerative diseases, such as HD. Moreover, differentiated neural cells can organize into three-dimensional (3D) organoids, mimicking the complex architecture of the brain. In this article, we present a comprehensive review of recent HD models, the methods for differentiating HD–iPSCs into the desired neural cell types, and the progress in gene editing techniques leading toward stem-cell-based therapy.

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“…Longer neuronal cultures can also be achieved by generating brain organoids. However, to date only two studies have modeled PD using PD-patient derived midbrain organoids (Kim et al, 2019;Smits et al, 2019) and cell death was reported in only one of these (Kim et al, 2019).…”

Section: Cell Deathmentioning

confidence: 99%

“…Another mitochondrial stressor inhibiting mitochondrial complex I, MPTP, also causes PD symptoms within days of exposure (Langston, 2017). An increased susceptibility towards rotenone (Cooper et al, 2012;Ryan et al, 2013;Flierl et al, 2014;Mittal et al, 2017;Tabata et al, 2018) and MPTP (Kim et al, 2019) was also determined in neurons and organoids from iPSC-derived PD patients'. Carbonyl cyanide m-chlorophenyl hydrazine (CCCP) decreases the mitochondrial membrane potential and PINK1 and PARK2 iPSC-derived DA neurons were more prone to cell death after treatment with CCCP (Chung et al, 2016).…”

Section: Stressor Responsementioning

confidence: 99%

“…Similar to the 2D differentiation of human iPSC-derived DA neurons, human midbrain organoids (hMOs) containing DA neurons are generated by patterning of iPSCs to midbrain fate. Either human iPSCs (Jo et al, 2016;Qian et al, 2016;Kim et al, 2019) or already patterned neural stem cells (Monzel et al, 2017;Smits et al, 2019) are aggregated as single cells to form hMOs.…”

Section: Organoidsmentioning

confidence: 99%

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Modeling Cell-Cell Interactions in Parkinson’s Disease Using Human Stem Cell-Based Models

Simmnacher

Lanfer

Rizo

et al. 2020

Front. Cell. Neurosci.

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Parkinson's disease (PD) is the most frequently occurring movement disorder, with an increasing incidence due to an aging population. For many years, the post-mortem brain was regarded as the gold standard for the analysis of the human pathology of this disease. However, modern stem cell technologies, including the analysis of patient-specific neurons and glial cells, have opened up new avenues for dissecting the pathologic mechanisms of PD. Most data on morphological changes, such as cell death or changes in neurite complexity, or functional deficits were acquired in 2D and few in 3D models. This review will examine the prerequisites for human disease modeling in PD, covering the generation of midbrain neurons, 3D organoid midbrain models, the selection of controls including genetically engineered lines, and the study of cell-cell interactions. We will present major disease phenotypes in human in vitro models of PD, focusing on those phenotypes that have been detected in genetic and sporadic PD models. An additional point covered in this review will be the use of induced pluripotent stem cell (iPSC)-derived technologies to model cell-cell interactions in PD.

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Modeling G2019S-LRRK2 Sporadic Parkinson's Disease in 3D Midbrain Organoids

Cited by 244 publications

References 43 publications

Unprecedented Potential for Neural Drug Discovery Based on Self-Organizing hiPSC Platforms

Unprecedented Potential for Neural Drug Discovery Based on Self-Organizing hiPSC Platforms

Recent Overview of the Use of iPSCs Huntington’s Disease Modeling and Therapy

Modeling Cell-Cell Interactions in Parkinson’s Disease Using Human Stem Cell-Based Models

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