2019
DOI: 10.1016/j.stem.2018.10.023
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Single-Cell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes

Abstract: SummaryInduced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson’s disease (PD), but neuronal cultures are confounded by asynchronous and heterogeneous appearance of disease phenotypes in vitro. Using high-resolution, single-cell transcriptomic analyses of iPSC-derived dopamine neurons carrying the GBA-N370S PD risk variant, we identified a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Pseudotime analysis of genes differenti… Show more

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Cited by 139 publications
(126 citation statements)
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“…Taken together, these results suggest that HDACs 4 and 5 redundantly act in the same pathway that restricts the induction of activitydependent transcriptional programs, thereby limiting the numbers of neurons that undergo structural and/or functional plasticity in response to sensory input. In conjunction with reports that documented aberrant nuclear retention of HDAC4 in cellular and animal models of Parkinson's disease and Ataxia telangiectasia 32,33 , our results also imply that class IIa HDACs may exert their effects via different mechanisms under the physiological and pathological conditions depending on kinetics of nuclear import/export. In other words, HDACs 4 and 5 are intrinsically capable of repressing a broad spectrum of targets and they evidently do so upon irreversible nuclear entry (Fig.…”
Section: Discussionsupporting
confidence: 88%
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“…Taken together, these results suggest that HDACs 4 and 5 redundantly act in the same pathway that restricts the induction of activitydependent transcriptional programs, thereby limiting the numbers of neurons that undergo structural and/or functional plasticity in response to sensory input. In conjunction with reports that documented aberrant nuclear retention of HDAC4 in cellular and animal models of Parkinson's disease and Ataxia telangiectasia 32,33 , our results also imply that class IIa HDACs may exert their effects via different mechanisms under the physiological and pathological conditions depending on kinetics of nuclear import/export. In other words, HDACs 4 and 5 are intrinsically capable of repressing a broad spectrum of targets and they evidently do so upon irreversible nuclear entry (Fig.…”
Section: Discussionsupporting
confidence: 88%
“…Over the past few years, HDACs have attracted considerable interest as potential therapeutic targets, prompting the design and clinical implementation of small molecule inhibitors 21,[51][52][53] . However, the precise roles of class IIa HDACs in the nervous system have remained unclear, despite the evidence that loss or mis-localization of these proteins may lead to neurological abnormalities in model organisms and humans [25][26][27][28]30,32,33,35 . Unlike constitutively nuclear class I HDACs, vertebrate class IIa HDACs are unable to deacetylate histones due to evolutionarily acquired Tyrosine to Histidine substitution in the active site of the C-terminal enzymatic domain 20,24 .…”
Section: Discussionmentioning
confidence: 99%
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“…The early developmental mechanisms operating in the telencephalon are proximal to genetic risk for neurodevelopmental disorders including autism spectrum disorder (ASD) (Marchetto et al, 2016;Mariani et al, 2015), bipolar disorder (Madison et al, 2015), fragile X syndrome (Kwan et al, 2012a), Huntington's disease (Consortium, 2017) and brain cancers (Crawley et al, 2016;Ernst, 2016). In the context of an unprecedented transcriptomic and epigenetic mapping of the human central nervous system (Amiri et al, 2018;de la Torre-Ubieta et al, 2018;Wang et al, 2018;Zhu et al, 2018), progress continues in defining disease relevant in vitro phenotypes as a central tool in the development of novel therapeutic interventions (Fujimori et al, 2018;Hubler et al, 2018;Lang et al, 2018). To achieve accurate models of risk for neuropsychiatric disease, it will be valuable to assess how patient-specific iPSCs vary as they progress through the non-linear developmental transitions described here.…”
Section: Discussionmentioning
confidence: 99%
“…Evidence of genetic risk for neuropsychiatric disorders has been found in the patterns of genes expressed in the midfetal neurogenic cortex (Gulsuner et al, 2013;Parikshak et al, 2013;State and Sestan, 2012;Willsey et al, 2013;Xu et al, 2014). Moreover, risk associated genes have been identified in the in vitro functional phenotypes of NSCs derived from patient-specific induced pluripotent stem cells (iPSCs) (Brennand et al, 2015;Consortium, 2017;Fujimori et al, 2018;Lang et al, 2018;Madison et al, 2015;Marchetto et al, 2016;Mariani et al, 2015). Thus, understanding the signaling specifying cortical NSCs in vitro is required to define pathogenic mechanisms and develop new therapies for brain disorders.…”
Section: Introductionmentioning
confidence: 99%