Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data

Abstract

Huntington’s disease is a rare neurodegenerative disease caused by a cytosine–adenine–guanine (CAG) trinucleotide expansion in the Huntingtin (HTT) 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 CACNA1I gene was the mostly highly rewired node among pre-symptomatic and symptomatic HD network. Furthermore, we identified AF198444 to be common between the rewired genes and DEGs of symptomatic HD. CNTN6, DEK, LTN1, MST4, ZFYVE16, CEP135, DCAKD, MAP4K3, NUPL1 and RBM15 between the DEGs of pre-symptomatic and DEGs of symptomatic HD and CACNA1I, DNAJB14, EPS8L3, HSDL2, SNRPD3, SOX12, ACLY, ATF2, BAG5, ERBB4, FOCAD, GRAMD1C, LIN7C, MIR22, MTHFR, NABP1, NRG2, OTC, PRAMEF12, SLC30A10, STAG2 and Y16709 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 (Ca2+) signaling (pre-symptomatic), dopaminergic synapse pathway (symptomatic HD patients) and Hippo signaling (pre-symptomatic) pathways were identified. The in silico metabolites we identified include Ca2+, 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.

Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties

“…In line with our results, ARL8B, Tubb2A, Polr2 sub-units, Mlf2, GNL3, and Rad23B proteins were also found enriched in the insoluble fractions of Q175 HD mice brains 99 and Tubb2a in R6/2 mice 100 nuclear inclusions. Interestingly, the gene expression level of these nuclear proteins was also significantly increased in HD post-mortem brain (PCBD2) 101 and symptomatic HD patients (Mlf2, GNL3, Polr2, and ARL8B) 102 . Altogether, this suggests that the loss of key nuclear proteins due to their sequestration by the pathological Htt inclusion is compensated in neurons by increasing gene expression levels.…”

Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties

“…Interestingly, the gene expression level of these nuclear proteins was also significantly increased in HD post-mortem brain (PCBD2) 101 and symptomatic HD patients (Mlf2, GNL3, Polr2 and ARL8B) 102 . Altogether, this suggests that the loss of key nuclear proteins due to their sequestration by the pathological Htt inclusion is compensated in neurons by increasing gene expression levels.…”

Identification of Novel Serum Metabolic Biomarkers as Indicators in the Progression of Intravenous Leiomyomatosis: A High Performance Liquid Chromatography-Tandem Mass Spectrometry-Based Study

“…Metabolites are defined as small organic and low-molecular-weight compounds (<1,500 Dalton), which are the final products during the metabolic process ( Alonso et al, 2015 ). The study of metabolites helps to identify metabolic pathways that are activated or dysfunctional in patients ( Christodoulou et al, 2020 ). At the molecular level, metabolomics adopts novel biomarkers to explore the underlying mechanisms of disease development ( Wang et al, 2011 ).…”