iPSC modeling of young-onset Parkinson’s disease reveals a molecular signature of disease and novel therapeutic candidates

Laperle, Alex; Sances, Samuel; Yucer, Nur; Dardov, Victoria; Garcia, Veronica J.; Ho, Ritchie; Fulton, AnneB; Jones, Michelle R.; Roxas, Kristina; Avalos, Pablo; West, Destiny; Bañuelos, Maria G.; Zhan, Shuie; Murali, Ramachandran; Maidment, Nigel T.; Eyk, Jennifer E. Van; Tagliati, Michele; Svendsen, Clive N.

doi:10.1038/s41591-019-0739-1

Cited by 113 publications

(108 citation statements)

References 73 publications

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“…An hiPSC control line (02iCTR) was generated by the Cedars-Sinai Medical Center iPSC Core from peripheral blood mononuclear cells and shown to be fully pluripotent (Laperle et al, 2020).…”

Section: Human Induced Pluripotent Stem Cells Can Differentiate Into mentioning

confidence: 99%

“…The appropriate institutional review board (IRB) and stem cell research oversight committee (SCRO) were consulted at UCLA and Cedars-Sinai Medical Center. The 02iCTR hiPSC line was derived from human peripheral blood mononuclear cells and has been published previously (Laperle et al, 2020). This cell line was obtained from the Cedars-Sinai Medical Center iPSC core facility and was derived under their IRB-SCRO protocol "Pro00032834: iPSC Core Repository and Stem Cell Program".…”

Section: Hipsc Derivationmentioning

confidence: 99%

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Human iPSC-Derived Cardiomyocytes are Susceptible to SARS-CoV-2 Infection

Sharma

García

Arumugaswami

et al. 2020

Preprint

115

152

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words):Coronavirus disease 2019 is a viral pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is predominantly defined by respiratory symptoms, but cardiac complications including arrhythmias, heart failure, and viral myocarditis are also prevalent. Although the systemic ischemic and inflammatory responses caused by COVID-19 can detrimentally affect cardiac function, the direct impact of SARS-CoV-2 infection on human cardiomyocytes is not well-understood. We used human induced pluripotent stem cellderived cardiomyocytes (hiPSC-CMs) as a model system to examine the mechanisms of cardiomyocyte-specific infection by SARS-CoV-2. Microscopy and immunofluorescence demonstrated that SARS-CoV-2 can enter and replicate within hiPSC-CMs, localizing at perinuclear locations within the cytoplasm. Viral cytopathic effect induced hiPSC-CM apoptosis and cessation of beating after 72 hours of infection. These studies show that SARS-CoV-2 can infect hiPSC-CMs in vitro, establishing a model for elucidating the mechanisms of infection and potentially a cardiac-specific antiviral drug screening platform.was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

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“…An hiPSC control line (02iCTR) was generated by the Cedars-Sinai Medical Center iPSC Core from peripheral blood mononuclear cells and shown to be fully pluripotent (Laperle et al, 2020).…”

Section: Human Induced Pluripotent Stem Cells Can Differentiate Into mentioning

confidence: 99%

Section: Hipsc Derivationmentioning

confidence: 99%

Human iPSC-Derived Cardiomyocytes are Susceptible to SARS-CoV-2 Infection

Sharma

García

Arumugaswami

et al. 2020

Preprint

115

152

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“…Our results therefore support previous assertions that different genes/variants and inheritance patterns contribute to EOPD and LOPD 24 . While EOPD-specific molecular signatures have recently been uncovered 25 , more studies are needed to investigate the different etiologies in EOPD and LOPD.…”

Section: Discussionmentioning

confidence: 99%

Whole-exome analysis in Parkinson’s disease reveals a high burden of ultra rare variants in early onset cases

Bustos¹,

Krainc²,

Lubbe³

2020

Preprint

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Word count: Abstract = 208Main text = 4,362 (3,285 excluding Methods) ABSTRACTParkinson's disease (PD) is a complex neurodegenerative disorder with a strong genetic component. We performed a "hypothesis-free" exome-wide burden-based analysis of different variant frequencies, predicted functional impact and age of onset classes, in order to expand the understanding of rare variants in PD. Analyzing whole-exome data from a total of 1,425 PD cases and 596 controls, we found a significantly increased burden of ultra-rare (URV= private variants absent from gnomAD) protein altering variants (PAV) in early-onset PD cases (EOPD, <40 years old; P=3.95x10 -26 , beta=0.16, SE=0.02), compared to LOPD cases (>60 years old, late-onset), where more common PAVs (allele frequencies <0.001) showed the highest significance and effect (P=0.026, beta=0.15, SE=0.07). Gene-set burden analysis of URVs in EOPD highlighted significant disease-and tissue-relevant genes, pathways and protein-protein interaction networks that were different to that observed in non-EOPD cases. Heritability estimates revealed that URVs account for 15.9% of the genetic component in EOPD individuals. Our results suggest that URVs play a significant role in EOPD and that distinct etiological bases may exist for EOPD and sporadic PD. By providing new insights into the genetic architecture of PD, our study may inform approaches aimed at novel gene discovery and provide new directions for genetic risk assessment based on disease age of onset.

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“…In a recent issue of Nature Medicine , Svendsen and colleagues revealed a molecular signature of YOPD and identified a drug candidate for treating it by induced pluripotent stem cell (iPSC) modeling technology . Specifically, the authors first generated iPSCs from blood mononuclear cells of YOPD patients and subsequently induced them to differentiate into midbrain dopaminergic (mDA) cultures.…”

mentioning

confidence: 99%

“…This interesting study revealed the unique molecular signature in iPSC‐derived mDA cultures that may be used for early YOPD diagnostics. Importantly, this work provides a screening platform for discovery of novel therapeutic drugs for YOPD …”

mentioning

confidence: 99%