Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data
Huntington’s disease is a rare neurodegenerative disease caused by a cytosine–adenine–guanine (CAG) trinucleotide expansion in the Huntingtin (<i>HTT</i>) gene. Although Huntington’s disease (HD) is well studied, the pathophysiological mechanisms, genes and metabolites involved in HD rem...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-10-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/19/7414 |
| _version_ | 1797551534111719424 |
|---|---|
| author | Christiana C. Christodoulou Margarita Zachariou Marios Tomazou Evangelos Karatzas Christiana A. Demetriou Eleni Zamba-Papanicolaou George M. Spyrou |
| author_facet | Christiana C. Christodoulou Margarita Zachariou Marios Tomazou Evangelos Karatzas Christiana A. Demetriou Eleni Zamba-Papanicolaou George M. Spyrou |
| author_sort | Christiana C. Christodoulou |
| collection | DOAJ |
| description | Huntington’s disease is a rare neurodegenerative disease caused by a cytosine–adenine–guanine (CAG) trinucleotide expansion in the Huntingtin (<i>HTT</i>) gene. Although Huntington’s disease (HD) is well studied, the pathophysiological mechanisms, genes and metabolites involved in HD remain poorly understood. Systems bioinformatics can reveal synergistic relationships among different omics levels and enables the integration of biological data. It allows for the overall understanding of biological mechanisms, pathways, genes and metabolites involved in HD. The purpose of this study was to identify the differentially expressed genes (DEGs), pathways and metabolites as well as observe how these biological terms differ between the pre-symptomatic and symptomatic HD stages. A publicly available dataset from the Gene Expression Omnibus (GEO) was analyzed to obtain the DEGs for each HD stage, and gene co-expression networks were obtained for each HD stage. Network rewiring, highlights the nodes that change most their connectivity with their neighbors and infers their possible implication in the transition between different states. The <i>CACNA1I</i> gene was the mostly highly rewired node among pre-symptomatic and symptomatic HD network. Furthermore, we identified <i>AF198444</i> to be common between the rewired genes and DEGs of symptomatic HD. <i>CNTN6, DEK, LTN1, MST4, ZFYVE16, CEP135, DCAKD, MAP4K3, NUPL1</i> and <i>RBM15</i> between the DEGs of pre-symptomatic and DEGs of symptomatic HD and <i>CACNA1I, DNAJB14, EPS8L3, HSDL2, SNRPD3, SOX12, ACLY, ATF2, BAG5, ERBB4, FOCAD, GRAMD1C, LIN7C, MIR22, MTHFR, NABP1, NRG2, OTC, PRAMEF12, SLC30A10, STAG2</i> and <i>Y16709</i> between the rewired genes and DEGs of pre-symptomatic HD. The proteins encoded by these genes are involved in various biological pathways such as phosphatidylinositol-4,5-bisphosphate 3-kinase activity, cAMP response element-binding protein binding, protein tyrosine kinase activity, voltage-gated calcium channel activity, ubiquitin protein ligase activity, adenosine triphosphate (ATP) binding, and protein serine/threonine kinase. Additionally, prominent molecular pathways for each HD stage were then obtained, and metabolites related to each pathway for both disease stages were identified. The transforming growth factor beta (TGF-β) signaling (pre-symptomatic and symptomatic stages of the disease), calcium (Ca<sup>2+</sup>) signaling (pre-symptomatic), dopaminergic synapse pathway (symptomatic HD patients) and Hippo signaling (pre-symptomatic) pathways were identified. The in silico metabolites we identified include Ca<sup>2+</sup>, inositol 1,4,5-trisphosphate, sphingosine 1-phosphate, dopamine, homovanillate and L-tyrosine. The genes, pathways and metabolites identified for each HD stage can provide a better understanding of the mechanisms that become altered in each disease stage. Our results can guide the development of therapies that may target the altered genes and metabolites of the perturbed pathways, leading to an improvement in clinical symptoms and hopefully a delay in the age of onset. |
| first_indexed | 2024-03-10T15:47:29Z |
| format | Article |
| id | doaj.art-190658a493e2471f9e4cb5cc59d1a9d5 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T15:47:29Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-190658a493e2471f9e4cb5cc59d1a9d52023-11-20T16:21:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012119741410.3390/ijms21197414Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics DataChristiana C. Christodoulou0Margarita Zachariou1Marios Tomazou2Evangelos Karatzas3Christiana A. Demetriou4Eleni Zamba-Papanicolaou5George M. Spyrou6Bioinformatics Department; Cyprus Institute of Neurology and Genetics; Cyprus School of Molecular Medicine, 2371 Nicosia, CyprusBioinformatics Department; Cyprus Institute of Neurology and Genetics; Cyprus School of Molecular Medicine, 2371 Nicosia, CyprusBioinformatics Department; Cyprus Institute of Neurology and Genetics; Cyprus School of Molecular Medicine, 2371 Nicosia, CyprusDepartment of Informatics and Telecommunications, University of Athens, 157 72 Athens, GreeceDepartment of Primary Care and Population Health, University of Nicosia, 2417 Nicosia, CyprusNeurology Clinic D; Cyprus Institute of Neurology and Genetics; Cyprus School of Molecular Medicine, 2371 Nicosia, CyprusBioinformatics Department; Cyprus Institute of Neurology and Genetics; Cyprus School of Molecular Medicine, 2371 Nicosia, CyprusHuntington’s disease is a rare neurodegenerative disease caused by a cytosine–adenine–guanine (CAG) trinucleotide expansion in the Huntingtin (<i>HTT</i>) gene. Although Huntington’s disease (HD) is well studied, the pathophysiological mechanisms, genes and metabolites involved in HD remain poorly understood. Systems bioinformatics can reveal synergistic relationships among different omics levels and enables the integration of biological data. It allows for the overall understanding of biological mechanisms, pathways, genes and metabolites involved in HD. The purpose of this study was to identify the differentially expressed genes (DEGs), pathways and metabolites as well as observe how these biological terms differ between the pre-symptomatic and symptomatic HD stages. A publicly available dataset from the Gene Expression Omnibus (GEO) was analyzed to obtain the DEGs for each HD stage, and gene co-expression networks were obtained for each HD stage. Network rewiring, highlights the nodes that change most their connectivity with their neighbors and infers their possible implication in the transition between different states. The <i>CACNA1I</i> gene was the mostly highly rewired node among pre-symptomatic and symptomatic HD network. Furthermore, we identified <i>AF198444</i> to be common between the rewired genes and DEGs of symptomatic HD. <i>CNTN6, DEK, LTN1, MST4, ZFYVE16, CEP135, DCAKD, MAP4K3, NUPL1</i> and <i>RBM15</i> between the DEGs of pre-symptomatic and DEGs of symptomatic HD and <i>CACNA1I, DNAJB14, EPS8L3, HSDL2, SNRPD3, SOX12, ACLY, ATF2, BAG5, ERBB4, FOCAD, GRAMD1C, LIN7C, MIR22, MTHFR, NABP1, NRG2, OTC, PRAMEF12, SLC30A10, STAG2</i> and <i>Y16709</i> between the rewired genes and DEGs of pre-symptomatic HD. The proteins encoded by these genes are involved in various biological pathways such as phosphatidylinositol-4,5-bisphosphate 3-kinase activity, cAMP response element-binding protein binding, protein tyrosine kinase activity, voltage-gated calcium channel activity, ubiquitin protein ligase activity, adenosine triphosphate (ATP) binding, and protein serine/threonine kinase. Additionally, prominent molecular pathways for each HD stage were then obtained, and metabolites related to each pathway for both disease stages were identified. The transforming growth factor beta (TGF-β) signaling (pre-symptomatic and symptomatic stages of the disease), calcium (Ca<sup>2+</sup>) signaling (pre-symptomatic), dopaminergic synapse pathway (symptomatic HD patients) and Hippo signaling (pre-symptomatic) pathways were identified. The in silico metabolites we identified include Ca<sup>2+</sup>, inositol 1,4,5-trisphosphate, sphingosine 1-phosphate, dopamine, homovanillate and L-tyrosine. The genes, pathways and metabolites identified for each HD stage can provide a better understanding of the mechanisms that become altered in each disease stage. Our results can guide the development of therapies that may target the altered genes and metabolites of the perturbed pathways, leading to an improvement in clinical symptoms and hopefully a delay in the age of onset.https://www.mdpi.com/1422-0067/21/19/7414huntington’s diseasesystems bioinformaticspathwaysmetabolitesgene co-expressionnetwork biology |
| spellingShingle | Christiana C. Christodoulou Margarita Zachariou Marios Tomazou Evangelos Karatzas Christiana A. Demetriou Eleni Zamba-Papanicolaou George M. Spyrou Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data International Journal of Molecular Sciences huntington’s disease systems bioinformatics pathways metabolites gene co-expression network biology |
| title | Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data |
| title_full | Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data |
| title_fullStr | Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data |
| title_full_unstemmed | Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data |
| title_short | Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data |
| title_sort | investigating the transition of pre symptomatic to symptomatic huntington s disease status based on omics data |
| topic | huntington’s disease systems bioinformatics pathways metabolites gene co-expression network biology |
| url | https://www.mdpi.com/1422-0067/21/19/7414 |
| work_keys_str_mv | AT christianacchristodoulou investigatingthetransitionofpresymptomatictosymptomatichuntingtonsdiseasestatusbasedonomicsdata AT margaritazachariou investigatingthetransitionofpresymptomatictosymptomatichuntingtonsdiseasestatusbasedonomicsdata AT mariostomazou investigatingthetransitionofpresymptomatictosymptomatichuntingtonsdiseasestatusbasedonomicsdata AT evangeloskaratzas investigatingthetransitionofpresymptomatictosymptomatichuntingtonsdiseasestatusbasedonomicsdata AT christianaademetriou investigatingthetransitionofpresymptomatictosymptomatichuntingtonsdiseasestatusbasedonomicsdata AT elenizambapapanicolaou investigatingthetransitionofpresymptomatictosymptomatichuntingtonsdiseasestatusbasedonomicsdata AT georgemspyrou investigatingthetransitionofpresymptomatictosymptomatichuntingtonsdiseasestatusbasedonomicsdata |