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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...
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... compared the novel gene expression pattern in HD with huge control samples from BA9 and various tissues (GTEX consortium data) to examine whether the disease sample gene expression differs from the control tissues. The comparison of novel gene expression patterns with GTEX and other tissue control samples is shown in Figure 5. It is observed that the gene expression pattern of HD differs from that of the controls and also normal samples from other brain tissues. ...
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... Though there is some understanding of the involvement of huntingtin in a variety of intracellular processes, a comprehensive approach is required to recognize its role in cell biology. Complex disorders such as Huntington's disease are studied using omics technologies [8,9]: transcriptomics [10], proteomics [11,12] and metabolomics [13][14][15][16], however the HD secretome remains unstudied. ...
Huntington's disease is a hereditary incurable neurodegenerative disease caused by expansion of the polyglutamine tract in exon 1 of the huntingtin gene. Huntingtin is a large protein involved in many cellular processes, such as division, transport and secretion. Mutations in the protein lead to disruption of many cellular processes, including secretion, but differences in the composition of the secretome of cells in normal conditions and in Huntington's disease remain poorly studied. Since huntingtin is expressed at high levels in peripheral tissues and in the skin, we have focused our attention on the study of secretome produced by dermal fibroblasts. In order to identify differences in secreted factors caused by the huntingtin mutation we used tandem time-of-flight mass spectrometry. Forty-two differential proteins were identified in the secretomes of dermal fibroblasts from healthy donor and patient with Huntington's disease. We examine several proteins of interest including filamin A, periostin, ACTN4, BASP1, adrenomedullin, HSP70 and 14-3-3, whose expression is associated with processes such as cytoskeletal organization, cell adhesion, proliferation, cell migration, protein binding and regulation of cytoskeletal structure. HSP70 and 14-3-3 have neuroprotective properties, and interestingly, their expression was not detected in the secretome of cells with Huntington's disease. Thus, it was shown that the set of proteins secreted into the extracellular space by dermal fibroblasts with the Huntington's disease genotype differs from healthy cells, and the differences in cellular processes (proliferation, migration) observed in these cells in vitro are probably due to differences in the composition of the extracellular matrix which they synthesize.
... The importance of Hoxd9 as master regulator of neuronal cell fate is highlighted by its early transcriptional activation following NF-mediated rescue (Figures 1 and 3) [43]. In accordance with these results, previous studies have demonstrated that Hoxd9 regulates the expression of several genes involved in neuronal apoptosis, displaying increased expression in unfavorable brain tumors, whereas its loss of function causes defects in axonal targeting and reduction in neural cell numbers, suggesting its utility as a potential therapeutic target at the crossroads between neurodegeneration and cancer [111,[113][114][115]. To this regard, siRNA-induced silencing of Hoxd9 gene has been already employed to induce apoptosis in different types of brain tumors, including neuroblastoma [116,117]. ...
Transcriptional regulation is fundamental to most biological processes and reverse-engineering programs can be used to decipher the underlying programs. In this review, we describe how genomics is offering a systems biology-based perspective of the intricate and temporally coordinated transcriptional programs that control neuronal apoptosis and survival. In addition to providing a new standpoint in human pathology focused on the regulatory program, cracking the code of neuronal cell fate may offer innovative therapeutic approaches focused on downstream targets and regulatory networks. Similar to computers, where faults often arise from a software bug, neuronal fate may critically depend on its transcription program. Thus, cracking the code of neuronal life or death may help finding a patch for neurodegeneration and cancer.
Huntington's Disease (HD) is a rare, progressive neurodegenerative disease caused by CAG repeat expansion in the Huntingtin gene. HD is an incurable disease; therefore, there is a growing need for effective therapeutic treatments and candidate biomarkers for prognosis and diagnosis of HD. Technological advancements over the past couple of years, have led to high-throughput experiments and omics data. The use of System Bioinformatics (SB) approaches, allows for the integration of information across different-omics, this can clarify synergistic relationships across biological molecules, resulting in complex biological networks. SB and network-based approaches, are able to shed light on the potential interactions of genes, proteins, metabolites and pathways participating in HD pathogenesis and how dysregulation of these biological entities, can affect age on onset, disease severity and progression. Moreover, −omics data analysis and network-based approaches can provide better understanding how these biological molecules interact with each other and provides potential drug targets and biomarkers that can be used to treat HD or delay symptom onset; therefore, opening the door towards precision medicine. The aim of the following chapter, is to discuss the most popular-omics related to HD research, and the growing popularity of single cell analysis, repositories and software available for bulk and single cell analysis. In addition, network-based approaches regarding HD will also be mentioned.
