Correction: RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression

Labadorf, Adam; Hoss, Andrew G.; Lagomarsino, Valentina N.; Latourelle, Jeanne C.; Hadzi, Tiffany C.; Bregu, Joli; MacDonald, Marcy E.; Gusella, James F.; Chen, Jiang‐Fan; Akbarian, Schahram; Weng, Zhiping; Myers, Richard H.

doi:10.1371/journal.pone.0160295

Cited by 13 publications

(11 citation statements)

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“…The transcriptomic data of the dorsolateral prefrontal cortex (Brodmann Area 9) from the tissue of HD patients and control samples were obtained from the SRA database (SRP051844) [ 23 ]. These are human post-mortem samples, and the age of death for HD patients varies from 40 to 75 and 36 to 106 for healthy controls.…”

Section: Methodsmentioning

confidence: 99%

Integrative Meta-Analysis of Huntington’s Disease Transcriptome Landscape

Sneha

Dharshini

Taguchi

et al. 2022

Genes

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Huntington’s disease (HD) is a neurodegenerative disorder with autosomal dominant inheritance caused by glutamine expansion in the Huntingtin gene (HTT). Striatal projection neurons (SPNs) in HD are more vulnerable to cell death. The executive striatal population is directly connected with the Brodmann Area (BA9), which is mainly involved in motor functions. Analyzing the disease samples from BA9 from the SRA database provides insights related to neuron degeneration, which helps to identify a promising therapeutic strategy. Most gene expression studies examine the changes in expression and associated biological functions. In this study, we elucidate the relationship between variants and their effect on gene/downstream transcript expression. We computed gene and transcript abundance and identified variants from RNA-seq data using various pipelines. We predicted the effect of genome-wide association studies (GWAS)/ novel variants on regulatory functions. We found that many variants affect the histone acetylation pattern in HD, thereby perturbing the transcription factor networks. Interestingly, some variants affect miRNA binding as well as their downstream gene expression. Tissue-specific network analysis showed that mitochondrial, neuroinflammation, vasculature, and angiogenesis-related genes are disrupted in HD. From this integrative omics analysis, we propose that abnormal neuroinflammation acts as a two-edged sword that indirectly affects the vasculature and associated energy metabolism. Rehabilitation of blood-brain barrier functionality and energy metabolism may secure the neuron from cell death.

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Section: Methodsmentioning

confidence: 99%

Integrative Meta-Analysis of Huntington’s Disease Transcriptome Landscape

Sneha

Dharshini

Taguchi

et al. 2022

Genes

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“…This last study drew heavily from previously published databases from HD mouse models with transcriptional profiles associated with the striatal inflammatory response [158][159][160]. Morphologically, some pan-cellular HD models, e.g., R6/2, display an increased number of Iba1 positive cells in the striatum, particularly as compared to neuronal models, suggesting that MSN mHtt does not by itself induce microgliosis [29,161,162].…”

Section: Microglia/neuroinflammationmentioning

confidence: 99%

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

Creus-Muncunill

Ehrlich

2019

Neurotherapeutics

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Huntington's disease (HD) is an autosomal dominant disorder caused by an expansion in the trinucleotide CAG repeat in exon-1 in the huntingtin gene, located on chromosome 4. When the number of trinucleotide CAG exceeds 40 repeats, disease invariably is manifested, characterized by motor, cognitive, and psychiatric symptoms. The huntingtin (Htt) protein and its mutant form (mutant huntingtin, mHtt) are ubiquitously expressed but although multiple brain regions are affected, the most vulnerable brain region is the striatum. Striatal medium-sized spiny neurons (MSNs) preferentially degenerate, followed by the cortical pyramidal neurons located in layers V and VI. Proposed HD pathogenic mechanisms include, but are not restricted to, excitotoxicity, neurotrophic support deficits, collapse of the protein degradation mechanisms, mitochondrial dysfunction, transcriptional alterations, and disorders of myelin. Studies performed in cell type-specific and regionally selective HD mouse models implicate both MSN cell-autonomous properties and cell-cell interactions, particularly corticostriatal but also with non-neuronal cell types. Here, we review the intrinsic properties of MSNs that contribute to their selective vulnerability and in addition, we discuss how astrocytes, microglia, and oligodendrocytes, together with aberrant corticostriatal connectivity, contribute to HD pathophysiology. In addition, mHtt causes cell-autonomous dysfunction in cell types other than MSNs. These findings have implications in terms of therapeutic strategies aimed at preventing neuronal dysfunction and degeneration.

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“…High expression of PLD1 and SLC7A2 was reported to be a characteristic of AD brain [ 71 , 72 ] while SLC7A2 was also found to be upregulated in human HD brain. [ 73 ] Moreover, an earlier study had depicted that SH3PXD2A is associated with ADAM12 to enhance neurotoxicity during the progression of AD. [ 74 ] Whereas, most of these 13 downregulated miRNAs were already reported to be useful for the brain, for example, hsa‐mir‐125a was found to interfere with the viral translation process.…”

Section: Discussionmentioning

confidence: 99%

Deregulation of ceRNA Networks in Frontal Cortex and Choroid Plexus of Brain during SARS‐CoV‐2 Infection Aggravates Neurological Manifestations: An Insight from Bulk and Single‐Cell Transcriptomic Analyses

Das

Podder

2022

Advanced Biology

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CSF) of patients with Parkinson's disease (PD) [5] and found to be potent in causing neurodegeneration by invading the neurons. [6] SARS-CoV-2 belongs to the family of these coronaviruses and it was also found to be neuro-invasive. [7] In addition to that, the cytokine storm due to SARS-CoV-2 infection is massively exhibited by a hyperinflammatory response. [8] The chronic neuroinflammation induced by cytokine storm is also being treated as a marker of neurodegenerative diseases like Alzheimer's (AD), PD, and Huntington's disease (HD). [9] During AD progression, pro-inflammatory cytokines like IL-1 and IL-6 inhibit phagocytosis of beta-amyloid (Aβ) by microglia and so its accumulation causes neuroinflammation. [10] Whereas, in CSF of PD patients, tumor necrosis factor (TNF) was reported to be responsible for neuronal death in fatal cases. [11] Intriguingly, neuroinflammation was also found to instigate psychiatric diseases by elicitation of microglial response, altering neuroplasticity, cognition, and behavior. [12] Thus, aggravation of neuroinflammatory responses by cytokine storm of SARS-CoV-2 might cause neurological manifestations in the future.As per reports from the epicenter of COVID-19-Wuhan, China, the most common neurological manifestation of SARS-CoV-2 included dizziness, headache, impaired consciousness, seizures, and acute cerebrovascular disease. [13] A recent report suggested that a COVID-19 patient symptomized by fever and abnormal mental status was diagnosed with acute necrotizing encephalopathy which is characterized by blood-brain barrier (BBB) disruption due to intracranial cytokine storm. [14] Hence, neurological manifestations are emerging as an aftermath of COVID-19. Due to the lack of experimental studies in pandemic situation, in silico studies have been priming COVID-19 research by digging into the utter complexities that might be associated with the comorbidities. [15,16] Several studies with human brain organoids reveal a varying degree of neurotropism for SARS-CoV-2. [17,18] Since the brain is a complex heterogeneous tissue consisting of various cell types like-glial, epithelial, and neural cells, [19] so to understand neurological manifestations of SARS-CoV-2 infection, studies should be conducted at the Although transcriptomic studies of SARS-CoV-2-infected brains have depicted variability in gene expression, the landscape of deregulated cell-specific regulatory circuits has not been elucidated yet. Hence, bulk and single-cell RNA-seq data are analyzed to gain detailed insights. Initially, two ceRNA networks with 19 and 3 differentially expressed (DE) hub lncRNAs are reconstructed in SARS-CoV-2 infected Frontal Cortex (FC) and Choroid Plexus (CP), respectively. Functional and pathway enrichment analyses of downstream mRNAs of deregulated ceRNA axes demonstrate impairment of neurological processes. Mapping of hub lncRNA-mRNA pairs from bulk RNA-seq with snRNA-seq data has indicated that NORAD, NEAT1, and STXBP5-AS1 are downregulated across 4, 4, and 2 FC cell types, respectively. At ...

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Correction: RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression

Cited by 13 publications

References 1 publication

Integrative Meta-Analysis of Huntington’s Disease Transcriptome Landscape

Integrative Meta-Analysis of Huntington’s Disease Transcriptome Landscape

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

Deregulation of ceRNA Networks in Frontal Cortex and Choroid Plexus of Brain during SARS‐CoV‐2 Infection Aggravates Neurological Manifestations: An Insight from Bulk and Single‐Cell Transcriptomic Analyses

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