Gene co-expression network analysis for identifying genetic markers in Parkinson's disease - a three-way comparative approach

George, Gincy; Singh, Sachidanand; Lokappa, Sowmya Bekshe; Varkey, Jobin

doi:10.1016/j.ygeno.2018.05.005

Cited by 53 publications

(29 citation statements)

References 76 publications

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“…Heterogeneity between idiopathic patients is expected in a disease with complex polygenic inheritance, leading to a variable level of cell-autonomous effects in different individuals, and one might expect the genetic contribution to be greater in some idiopathic patients than others. Our findings are consistent with recent studies (Hsieh et al., 2016, Sánchez-Danés et al., 2012, Nenasheva et al., 2017, Tolosa et al., 2018, George et al., 2018), which have found cellular phenotypes or transcriptomic perturbations in iPSC-derived dopamine neurons from idiopathic PD patients.…”

Section: Discussionsupporting

confidence: 94%

Single-Cell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes

et al. 2019

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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 differentially expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with HDAC4-modulating compounds upregulated genes early in the DE axis and corrected PD-related cellular phenotypes. Our study demonstrates how single-cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets.

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Section: Discussionsupporting

confidence: 94%

Single-Cell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes

et al. 2019

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“…Overexpression in neurodegenerative diseases [31,[36][37][38][39][40][41][42][43][44][45][46][47][48]…”

Section: Neurodegenerationmentioning

confidence: 99%

“…Sorcin sequestration by aberrant forms of tau results in impaired calcium homeostasis and resistance to ER stress and may contribute to AD progression [31]. Sorcin is also overexpressed in frontal cortex tissues from frontotemporal dementia, with respect to control patients [42], in substantia nigra of Parkinson's disease (PD) patients vs. controls [43], and in mitochondrial proteins from substantia nigra pars compacta pathologically verified PD patients vs. controls [44], is upregulated in MPP + -treated cells [36], and in induced pluripotent stem cells (iPSCs) derived from PD patients vs. control cells [45]. Sorcin is overexpressed in seven human and mouse models of Huntington's disease, under the control of the ERSE-I (ER stress response element) promoter upstream sorcin gene, together with other proteins involved in ER stress and unfolded protein response [46].…”

Section: Sorcin Under Cellular Stressing Conditions and In Pathologiesmentioning

confidence: 99%

Roles of Sorcin in Drug Resistance in Cancer: One Protein, Many Mechanisms, for a Novel Potential Anticancer Drug Target

Battista

Fiorillo

Chiarini

et al. 2020

Cancers

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The development of drug resistance is one of the main causes of failure in anti-cancer treatments. Tumor cells adopt many strategies to counteract the action of chemotherapeutic agents, e.g., enhanced DNA damage repair, inactivation of apoptotic pathways, alteration of drug targets, drug inactivation, and overexpression of ABC (Adenosine triphosphate-binding cassette, or ATP-binding cassette) transporters. These are broad substrate-specificity ATP-dependent efflux pumps able to export toxins or drugs out of cells; for instance, ABCB1 (MDR1, or P-glycoprotein 1), overexpressed in most cancer cells, confers them multidrug resistance (MDR). The gene coding for sorcin (SOluble Resistance-related Calcium-binding proteIN) is highly conserved among mammals and is located in the same chromosomal locus and amplicon as the ABC transporters ABCB1 and ABCB4, both in human and rodent genomes (two variants of ABCB1, i.e., ABCB1a and ABCB1b, are in rodent amplicon). Sorcin was initially characterized as a soluble protein overexpressed in multidrug (MD) resistant cells and named “resistance-related” because of its co-amplification with ABCB1. Although for years sorcin overexpression was thought to be only a by-product of the co-amplification with ABC transporter genes, many papers have recently demonstrated that sorcin plays an important part in MDR, indicating a possible role of sorcin as an oncoprotein. The present review illustrates sorcin roles in the generation of MDR via many mechanisms and points to sorcin as a novel potential target of different anticancer molecules.

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“…Sorcin is overexpressed in substantia nigra of PD patients vs. controls 39 , and in substantia nigra pars compacta pathologically verified PD patients vs. controls 40 , is up-regulated in MPP + -treated cells 41 , and in induced pluripotent stem cells (iPSCs) derived from PD patients vs. control cells 42 . Further, Sorcin is among the genes overexpressed in 7 human and mouse models of Huntington’s disease, under the control of the ERSE-I (ER stress response element) promoter upstream Sorcin gene, together with other proteins involved in ER stress and unfolded protein response 43 .…”

Section: Introductionmentioning

confidence: 99%

Sorcin is an early marker of neurodegeneration, Ca2+ dysregulation and endoplasmic reticulum stress associated to neurodegenerative diseases

et al. 2020

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Dysregulation of calcium signaling is emerging as a key feature in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), and targeting this process may be therapeutically beneficial. Under this perspective, it is important to study proteins that regulate calcium homeostasis in the cell. Sorcin is one of the most expressed calcium-binding proteins in the human brain; its overexpression increases endoplasmic reticulum (ER) calcium concentration and decreases ER stress in the heart and in other cellular types. Sorcin has been hypothesized to be involved in neurodegenerative diseases, since it may counteract the increased cytosolic calcium levels associated with neurodegeneration. In the present work, we show that Sorcin expression levels are strongly increased in cellular, animal, and human models of AD, PD, and HD, vs. normal cells. Sorcin partially colocalizes with RyRs in neurons and microglia cells; functional experiments with microsomes containing high amounts of RyR2 and RyR3, respectively, show that Sorcin is able to regulate these ER calcium channels. The molecular basis of the interaction of Sorcin with RyR2 and RyR3 is demonstrated by SPR. Sorcin also interacts with other ER proteins as SERCA2 and Sigma-1 receptor in a calcium-dependent fashion. We also show that Sorcin regulates ER calcium transients: Sorcin increases the velocity of ER calcium uptake (increasing SERCA activity). The data presented here demonstrate that Sorcin may represent both a novel early marker of neurodegenerative diseases and a response to cellular stress dependent on neurodegeneration.

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Gene co-expression network analysis for identifying genetic markers in Parkinson's disease - a three-way comparative approach

Cited by 53 publications

References 76 publications

Single-Cell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes

Single-Cell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes

Roles of Sorcin in Drug Resistance in Cancer: One Protein, Many Mechanisms, for a Novel Potential Anticancer Drug Target

Sorcin is an early marker of neurodegeneration, Ca2+ dysregulation and endoplasmic reticulum stress associated to neurodegenerative diseases

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