Impairment of proteasome and anti-oxidative pathways in the induced pluripotent stem cell model for sporadic Parkinson's disease

Chang, Kuo‐Hsuan; Lee‐Chen, Guey‐Jen; Wu, Yih‐Ru; Chen, Yijing; Lin, Jia Li; Li, Meng; Chen, I-Cheng; Lo, Yen-Shi; Wu, Huey-Dong; Chen, Chiung‐Mei

doi:10.1016/j.parkreldis.2016.01.001

Cited by 36 publications

(47 citation statements)

References 23 publications

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“…Another study found altered ERK signaling in derived dopaminergic neurons that, when repressed, was able to reverse a certain disease pathology, such as sensitivity to oxidative stress and neurite shortening [87]. Also, proteasome dysfunction, oxidative stress, and increased expression of a-synuclein have been observed in PARK2 mutant hiPSC-derived neurons [88]; however, no Lewy body formation or neurodegeneration has been recapitulated in hiPSC-derived dopaminergic neurons. Also, AD [89,90] and HD [91] have been mimicked in the dish and reproduced important disease phenotypes.…”

Section: Using Pscs For Modeling Neurovascular Diseasementioning

confidence: 99%

Paving the Way Toward Complex Blood-Brain Barrier Models Using Pluripotent Stem Cells

Lauschke

Frederiksen

Hall

2017

Stem Cells and Development

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Section: Using Pscs For Modeling Neurovascular Diseasementioning

confidence: 99%

Paving the Way Toward Complex Blood-Brain Barrier Models Using Pluripotent Stem Cells

Lauschke

Frederiksen

Hall

2017

Stem Cells and Development

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“…Importantly, accumulation of α‐syn does not represent a LRRK2‐specific pathophenotype as similar data have been generated for various different models of familial PD, including iPSC models for triplication of the SNCA gene (SNCA trp ) (Byers et al., ; Flierl et al., ; Mazzulli, Zunke, Isacson, Studer, & Krainc, ), the SNCA A53T point mutation (Kouroupi et al., ; Mazzulli, Zunke, Tsunemi et al., ; Ryan et al., ), mutations in GBA (Woodard et al., ), PRKN (Chang et al., ; Chung et al., ; Shaltouki et al., ) and PINK1 (Chung et al., ), in homozygous DJ‐1 mutant cells and in DJ‐1 knock‐out neurons (Burbulla et al., ) as well as in iPSC‐derived neurons from an idiopathic PD (iPD) patient (Mazzulli, Zunke, Isacson et al., ).…”

Section: Pd‐associated Lrrk2 Variants In Ipsc‐based Disease Modelingmentioning

confidence: 79%

Induced pluripotent stem cell‐based modeling of mutant LRRK2‐associated Parkinson's disease

Weykopf

Haupt

Jungverdorben

et al. 2019

Eur J of Neuroscience

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Recent advances in cell reprogramming have enabled assessment of disease‐related cellular traits in patient‐derived somatic cells, thus providing a versatile platform for disease modeling and drug development. Given the limited access to vital human brain cells, this technology is especially relevant for neurodegenerative disorders such as Parkinson's disease (PD) as a tool to decipher underlying pathomechanisms. Importantly, recent progress in genome‐editing technologies has provided an ability to analyze isogenic induced pluripotent stem cell (iPSC) pairs that differ only in a single genetic change, thus allowing a thorough assessment of the molecular and cellular phenotypes that result from monogenetic risk factors. In this review, we summarize the current state of iPSC‐based modeling of PD with a focus on leucine‐rich repeat kinase 2 (LRRK2), one of the most prominent monogenetic risk factors for PD linked to both familial and idiopathic forms. The LRRK2 protein is a primarily cytosolic multi‐domain protein contributing to regulation of several pathways including autophagy, mitochondrial function, vesicle transport, nuclear architecture and cell morphology. We summarize iPSC‐based studies that contributed to improving our understanding of the function of LRRK2 and its variants in the context of PD etiopathology. These data, along with results obtained in our own studies, underscore the multifaceted role of LRRK2 in regulating cellular homeostasis on several levels, including proteostasis, mitochondrial dynamics and regulation of the cytoskeleton. Finally, we expound advantages and limitations of reprogramming technologies for disease modeling and drug development and provide an outlook on future challenges and expectations offered by this exciting technology.

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“…This study also showed higher basal and toxin‐induced NO levels in neurons derived from patients harboring the A53T mutation (Chung et al., ; Ryan et al., ) Midbrain neurons derived from IPSCs of patients carrying the A53T mutation exhibit increased oxidative stress induced by environmental toxins as compared to their isogenic controls which eventually leads to cell death (Ryan et al., ). In neurons derived from IPSCs from sporadic early onset PD patients carrying a heterozygous deletion of exon 5 (Ex5del) in PARK2, the anti‐oxidative pathways are downregulated (Chang et al., ). Neurons derived from LRRK2 G2019S‐IPSC's show increased expression of oxidative stress response genes and are more susceptible to cell death caused by oxidative stress inducing agents such as hydrogen peroxide and 6‐hydroxydopamine, and a proteasome inhibitor MG132 then control DA neurons(Nguyen et al., ).…”

Section: Evidence Of Oxidative Stress In Ipsc Models Of Pdmentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in induced pluripotent stem cell models of Parkinson's disease

Bose

Beal

2018

Eur J of Neuroscience

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Parkinson's disease (PD) is the second most common neurodegenerative disease. Two percent of the population above the age of 60 is affected by the disease. The pathological hallmarks of PD include loss of dopaminergic neurons and the presence of Lewy bodies. Mitochondrial dysfunction and oxidative stress are thought to play a pivotal role in both sporadic and familial forms of the disease. In this review we focus on the role of mitochondrial dysfunction and oxidative stress in induced pluripotent stem cell (IPSC) models of PD.We also provide an overview of therapeutics that have been tested and some possible new therapeutics that can be tested in IPSC models of PD.

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Impairment of proteasome and anti-oxidative pathways in the induced pluripotent stem cell model for sporadic Parkinson's disease

Cited by 36 publications

References 23 publications

Paving the Way Toward Complex Blood-Brain Barrier Models Using Pluripotent Stem Cells

Paving the Way Toward Complex Blood-Brain Barrier Models Using Pluripotent Stem Cells

Induced pluripotent stem cell‐based modeling of mutant LRRK2‐associated Parkinson's disease

Mitochondrial dysfunction and oxidative stress in induced pluripotent stem cell models of Parkinson's disease

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