Delayed Cell Cycle Progression in STHdh&lt;sup&gt;Q111&lt;/sup&gt;/Hdh&lt;sup&gt;Q111&lt;/sup&gt; Cells, a Cell Model for Huntington’s Disease Mediated by microRNA-19a, microRNA-146a and microRNA-432

Das, Eashita; Jana, Nihar Ranjan; Bhattacharyya, Nitai P.

doi:10.2174/2211536604666150713105606

Cited by 18 publications

(14 citation statements)

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“…The intensity of the color depicts the strength of the correlation Cell cycle and protein transport (green module) were positively correlated with motor score and CAG repeat. Recent studies in mouse models of HD suggest that abnormalities in the cell cycle may contribute to the HD pathogenesis [ 32 , 33 ]. Sphingolipid biosynthetic process (thistle2 module) was positively correlated with TFC score and negatively correlated with motor score.…”

Section: Resultsmentioning

confidence: 99%

Common disease signatures from gene expression analysis in Huntington’s disease human blood and brain

Mina

Roon-Mom

Hettne

et al. 2016

Orphanet J Rare Dis

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BackgroundHuntington’s disease (HD) is a devastating brain disorder with no effective treatment or cure available. The scarcity of brain tissue makes it hard to study changes in the brain and impossible to perform longitudinal studies. However, peripheral pathology in HD suggests that it is possible to study the disease using peripheral tissue as a monitoring tool for disease progression and/or efficacy of novel therapies. In this study, we investigated if blood can be used to monitor disease severity and progression in brain. Since previous attempts using only gene expression proved unsuccessful, we compared blood and brain Huntington’s disease signatures in a functional context.MethodsMicroarray HD gene expression profiles from three brain regions were compared to the transcriptome of HD blood generated by next generation sequencing. The comparison was performed with a combination of weighted gene co-expression network analysis and literature based functional analysis (Concept Profile Analysis). Uniquely, our comparison of blood and brain datasets was not based on (the very limited) gene overlap but on the similarity between the gene annotations in four different semantic categories: “biological process”, “cellular component”, “molecular function” and “disease or syndrome”.ResultsWe identified signatures in HD blood reflecting a broad pathophysiological spectrum, including alterations in the immune response, sphingolipid biosynthetic processes, lipid transport, cell signaling, protein modification, spliceosome, RNA splicing, vesicle transport, cell signaling and synaptic transmission. Part of this spectrum was reminiscent of the brain pathology. The HD signatures in caudate nucleus and BA4 exhibited the highest similarity with blood, irrespective of the category of semantic annotations used. BA9 exhibited an intermediate similarity, while cerebellum had the least similarity. We present two signatures that were shared between blood and brain: immune response and spinocerebellar ataxias.ConclusionsOur results demonstrate that HD blood exhibits dysregulation that is similar to brain at a functional level, but not necessarily at the level of individual genes. We report two common signatures that can be used to monitor the pathology in brain of HD patients in a non-invasive manner. Our results are an exemplar of how signals in blood data can be used to represent brain disorders. Our methodology can be used to study disease specific signatures in diseases where heterogeneous tissues are involved in the pathology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0475-2) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Common disease signatures from gene expression analysis in Huntington’s disease human blood and brain

Mina

Roon-Mom

Hettne

et al. 2016

Orphanet J Rare Dis

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“…Modified interactions of transcription factors with wild-type HTT, direct binding of mutant HTT with DNA and epigenetic changes could contribute to the deregulation of genes in HD [4,5]. Differential levels of microRNA (miRNA), generally a negative regulator of a protein-coding gene, has also been identified in HD models and post-mortem brains of HD patients and other neurodegenerative diseases [4][5][6][7][8][9][10][11][12][13][14][15][16]. In cellular models, some of these miRNAs have been shown to modulate neuronal survival [9], disease progression by influencing neurogenesis [10], cell cycle [11][12][13], mitochondrial dynamics [14] and target HTT [16].…”

Section: Introductionmentioning

confidence: 99%

Altered Levels of Long NcRNAs Meg3 and Neat1 in Cell And Animal Models Of Huntington’s Disease

et al. 2018

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Altered expression levels of protein-coding genes and microRNAs have been implicated in the pathogenesis of Huntington's disease (HD). The involvement of other ncRNAs, especially long ncRNAs (lncRNA), is being realized recently and the related knowledge is still rudimentary. Using small RNA sequencing and PCR arrays we observed perturbations in the levels of 12 ncRNAs in HD mouse brain, eight of which had human homologs. Of these, Meg3, Neat1, and Xist showed a consistent and significant increase in HD cell and animal models. Transient knock-down of Meg3 and Neat1 in cell models of HD led to a significant decrease of aggregates formed by mutant huntingtin and downregulation of the endogenous Tp53 expression. Understanding Meg3 and Neat1 functions in the context of HD pathogenesis is likely to open up new strategies to control the disease.

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“…Most of the previous studies on the striatal cell lines used in the present study focused on differences between the Q7Q7 and Q111Q111 cells, and did not analyze the heterozygous Q7Q111 cells [ 20 , 61 – 63 ]. HD pathology has been shown to result from a toxic gain of function from huntingtin with long polyQ tracts [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Reduced Levels of Proteasome Products in a Mouse Striatal Cell Model of Huntington’s Disease

et al. 2015

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Huntington’s disease is the result of a long polyglutamine tract in the gene encoding huntingtin protein, which in turn causes a large number of cellular changes and ultimately results in neurodegeneration of striatal neurons. Although many theories have been proposed, the precise mechanism by which the polyglutamine expansion causes cellular changes is not certain. Some evidence supports the hypothesis that the long polyglutamine tract inhibits the proteasome, a multiprotein complex involved in protein degradation. However, other studies report normal proteasome function in cells expressing long polyglutamine tracts. The controversy may be due to the methods used to examine proteasome activity in each of the previous studies. In the present study, we measured proteasome function by examining levels of endogenous peptides that are products of proteasome cleavage. Peptide levels were compared among mouse striatal cell lines expressing either 7 glutamines (STHdh Q7/Q7) or 111 glutamines in the huntingtin protein, either heterozygous (STHdh Q7/Q111) or homozygous (STHdh Q111/Q111). Both of the cell lines expressing huntingtin with 111 glutamines showed a large reduction in nearly all of the peptides detected in the cells, relative to levels of these peptides in cells homozygous for 7 glutamines. Treatment of STHdh Q7/Q7 cells with proteasome inhibitors epoxomicin or bortezomib also caused a large reduction in most of these peptides, suggesting that they are products of proteasome-mediated cleavage of cellular proteins. Taken together, these results support the hypothesis that proteasome function is impaired by the expression of huntingtin protein containing long polyglutamine tracts.

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Delayed Cell Cycle Progression in STHdh<sup>Q111</sup>/Hdh<sup>Q111</sup> Cells, a Cell Model for Huntington’s Disease Mediated by microRNA-19a, microRNA-146a and microRNA-432

Cited by 18 publications

References 0 publications

Common disease signatures from gene expression analysis in Huntington’s disease human blood and brain

Common disease signatures from gene expression analysis in Huntington’s disease human blood and brain

Altered Levels of Long NcRNAs Meg3 and Neat1 in Cell And Animal Models Of Huntington’s Disease

Reduced Levels of Proteasome Products in a Mouse Striatal Cell Model of Huntington’s Disease

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