Evaluating the SERCA2 and VEGF mRNAs as Potential Molecular Biomarkers of the Onset and Progression in Huntington’s Disease

Abstract

Abnormalities of intracellular Ca2+ homeostasis and signalling as well as the down-regulation of neurotrophic factors in several areas of the central nervous system and in peripheral tissues are hallmarks of Huntington’s disease (HD). As there is no therapy for this hereditary, neurodegenerative fatal disease, further effort should be made to slow the progression of neurodegeneration in patients through the definition of early therapeutic interventions. For this purpose, molecular biomarker(s) for monitoring disease onset and/or progression and response to treatment need to be identified. In the attempt to contribute to the research of peripheral candidate biomarkers in HD, we adopted a multiplex real-time PCR approach to analyse the mRNA level of targeted genes involved in the control of cellular calcium homeostasis and in neuroprotection. For this purpose we recruited a total of 110 subjects possessing the HD mutation at different clinical stages of the disease and 54 sex- and age-matched controls. This study provides evidence of reduced transcript levels of sarco-endoplasmic reticulum-associated ATP2A2 calcium pump (SERCA2) and vascular endothelial growth factor (VEGF) in peripheral blood mononuclear cells (PBMCs) of manifest and pre-manifest HD subjects. Our results provide a potentially new candidate molecular biomarker for monitoring the progression of this disease and contribute to understanding some early events that might have a role in triggering cellular dysfunctions in HD.

Huntington’s Disease: Calcium Dyshomeostasis and Pathology Models

“…Genomic studies conducted in various HD models have revealed significant differences in the mRNA levels of the genes encoding the proteins involved in intracellular Ca 2+ regulation, including calcium-binding proteins such as parvalbumin, calmodulin, calbindin, and hypocalcin, as well as ryanodine receptor type 1, the inositol trisphosphate receptor (InsP3R1), and different subunits of voltage-gated calcium channels (VGCCs) [ 88 - 91 ]. In particular, the level of mRNA in the sarco-endoplasmic reticulum-associated ATP2A2 calcium pump (SERCA2) was reduced in peripheral blood mononuclear cells in HD [ 92 ].…”

Longitudinal expression changes are weak correlates of disease progression in Huntington’s disease

“…One RNA was included from a previous study of inflammatory processes in lymphocytes ( Runne et al , 2007 ). Two further candidates were chosen from a study that considered Ca 2+ homeostasis and neuroprotection using mononuclear blood cells ( Cesca et al , 2015 ). Six genes were identified based on a study of metabolic- and cellular stress-related RNA measures in whole blood compared to other clinical, anthropometric and biochemical parameters ( Krzysztoń-Russjan et al , 2013 ).…”

“…Several exploratory studies have reported transcriptomic changes in Huntington’s disease blood and highlighted specific RNAs as potential biomarkers. These have used both genome-wide (microarray, DeepSAGE) and targeted reverse transcription real-time quantitative PCR gene expression analyses ( Borovecki et al , 2005 ; Runne et al , 2007 ; Lovrecic et al , 2010 ; Hu et al , 2011 ; Cesca et al , 2015 ; Mastrokolias et al , 2015 ). Despite the number of potential biomarkers identified, there has been little overlap between the reported signatures across these studies.…”

“…These data were analysed cross-sectionally at both timepoints and also used to construct a longitudinal analysis of gene expression and disease progression. Both of these analyses were then interrogated to identify novel candidate biomarker genes, and to test progressive differential expression of genes identified in previous studies, using publicly available datasets ( Borovecki et al , 2005 ; Runne et al , 2007 ; Lovrecic et al , 2010 ; Hu et al , 2011 ; Krzysztoń-Russjan et al , 2013 ; Träger et al , 2014 ; Cesca et al , 2015 ; Mastrokolias et al , 2015 ; Miller et al , 2016 ; Zadel et al , 2018 ), as well as an independent TRACK-HD sample cohort. Finally, we sought to shed new light on, or to reproduce previous evidence of, molecular mechanisms of Huntington’s disease pathogenesis identified using GSEA ( Hensman Moss et al , 2017 ).…”

Customized Dietary Intervention Avoids Unintentional Weight Loss and Modulates Circulating miRNAs Footprint in Huntington's Disease

“…Other genes having more than five GIs included Fbxw7, Tmed7, Chuk , and Mafb . The literature describes that several of these genes (i.e., Fxo3, Tp53 , and Vegfa ) are involved in HD . Whether the selected miRNAs described here were solely responsible for gene regulation remains to be determined and deserves further research.…”