Isogenic Human iPSC Parkinson’s Model Shows Nitrosative Stress-Induced Dysfunction in MEF2-PGC1α Transcription

Ryan, Scott D.; Dolatabadi, Nima; Chan, Shing Fai; Zhang, Xiaofei; Akhtar, Mohd Waseem; Parker, James D. A.; Soldner, Frank; Sunico, Carmen R.; Nagar, Saumya; Talantova, Maria; Lee, Brian; Lopez, Kevin; Nutter, Anthony; Shan, Bing; Molokanova, Elena; Zhang, Yaoyang; Han, Xuemei; Nakamura, Tomohiro; Masliah, Eliezer; Yates, John R.; Nakanishi, Norihiko; Andreyev, Alexander Y.; Okamoto, Shu-ichi; Jaenisch, Rudolf; Ambasudhan, Rajesh; Lipton, Stuart A.

doi:10.1016/j.cell.2013.12.004

Cited by 9 publications

(7 citation statements)

References 5 publications

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“…iPSCs allow for the creation of a disease-relevant cell type (e.g., neurons) from fibroblasts of a patient with a disease. This technology has opened new doors in studying cell typespecific effects of ND-related mutations 8,78,81,82 . Unlike tumorderived cell lines, iPSCs provide a relevant human cell type with a genetic background related directly to a patient with the disease.…”

Section: Extending Findings From 'Simple' Model Organismsmentioning

confidence: 99%

Combating neurodegenerative disease with chemical probes and model systems

2014

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The disheartening results of recent clinical trials for neurodegenerative disease (ND) therapeutics underscore the need for a more comprehensive understanding of the underlying disease biology before effective therapies can be devised. One hallmark of many NDs is a disruption in protein homeostasis. Therefore, investigating the role of protein homeostasis in these diseases is central to delineating their underlying pathobiology. Here, we review the seminal role that chemical biology has played in furthering the research on and treatment of dysfunctional protein homeostasis in NDs. We also discuss the vital and predictive role of model systems in identifying conserved homeostasis pathways and genes therein that are altered in neurodegeneration. Integrating approaches from chemical biology with the use of model systems yields a powerful toolkit with which to unravel the complexities of ND biology.

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Section: Extending Findings From 'Simple' Model Organismsmentioning

confidence: 99%

Combating neurodegenerative disease with chemical probes and model systems

2014

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“…26 Reinhardt et al 27 reported that the activity of extracellular-signal-regulated kinase 1/2 or ERK in DA neurons with G2019S substitution in LRRK2 is enhanced due to increased phosphorylation. Ryan et al 22 employed gene expression analysis to demonstrate that mutant a-synuclein alters the myocyte enhancer factor-2 (MEF2) (an important regulator of mitochondria) transcriptional pathway in DA neurons, and Chung et al 21 identified that mutant asynuclein induces nitrosative stress and ER malfunction in cortical neurons. Altogether, these findings are encouraging, as they could potentially lead to new translational approaches.…”

Section: Pd Modelsmentioning

confidence: 98%

“…17 PD in a dish using iPSCs Park et al 18 were the first to report the generation of PD iPSCs (from a sporadic patient), but this early work focused on technical aspects of the reprogramming method, and the disease phenotype was not explored. Subsequently, a number of groups have described iPSCs with mutations in SNCA, [19][20][21][22] LRRK2, 23-30 PINK1, 25,31-33 and PARK2 33-36 as well as iPSCs from idiopathic PD patients. 24,37 For a description of these iPSCs, the reprogramming strategy, differentiation protocols, [23][24][25]31,[38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] and the disease phenotypes, see Tables 1 to 4.…”

Section: Pd Modelsmentioning

confidence: 99%

“…Ever since, the number of reports using isogenic iPSCs has increased steadily, and this will likely become a standard approach in the field. 21,22,26,27,30 Nevertheless, gene editing with designer nucleases has the risk of off-target effects 65,66 and requires lengthy cell expansion that may increase the number of passages to a point in which the iPSCs become unstable. 59 Hence, exhaustive screening of iPSCs modified with designer nucleases is also necessary before comparative analysis.…”

Section: Differences Between Ipsc Clonesmentioning

confidence: 99%

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Solving the puzzle of Parkinson’s disease using induced pluripotent stem cells

Zhao

Luo

Tian

et al. 2014

Exp Biol Med (Maywood)

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The prevalence and incidence of Parkinson's disease (PD) is increasing due to a prolonged life expectancy. This highlights the need for a better mechanistic understanding and new therapeutic approaches. However, traditional in vitro and in vivo experimental models to study PD are suboptimal, thus hampering the progress in the field. The epigenetic reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) offers a unique way to overcome this problem, as these cells share many properties of embryonic stem cells (ESCs) including the potential to be transformed into different lineages. PD modeling with iPSCs is nowadays facilitated by the growing availability of high-efficiency neural-specific differentiation protocols and the possibility to correct or induce mutations as well as creating marker cell lines using designer nucleases. These technologies, together with steady advances in human genetics, will likely introduce profound changes in the way we interpret PD and develop new treatments. Here, we summarize the different PD iPSCs reported so far and discuss the challenges for disease modeling using these cell lines.

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“…Since the discovery that adult human somatic cells can be reprogrammed into induced pluripotent stem cells (iPSC) by overexpression of only four transcription factors (Takahashi et al, 2007), a new era of research has started. Recently, numerous studies using iPSC-derived neurons have been published, including iPSC-derived neurons to model neurodegenerative diseases (Israel et al, 2012;Mattis et al, 2012;Kaye and Finkbeiner, 2013;Ryan et al, 2013;Richard and Maragakis, 2014). These proof-of principle studies recapitulate the key aspects of the different pathologies, including aberrant synaptic abnormalities and functional deficits (Penzes et al, 2011;Hick et al, 2014;Wen et al, 2014).…”

Section: Introductionmentioning

confidence: 96%