A meta-analysis of transcriptomic profiles of Huntington’s disease patients

Abstract

Description of robust transcriptomic alterations in Huntington’s disease is essential to identify targets for biochemical studies and drug development. We analysed publicly available transcriptome data from the brain and blood of 220 HD patients and 241 healthy controls and identified 737 and 661 genes with robustly altered mRNA levels in the brain and blood of HD patients, respectively. In the brain, a subnetwork of 320 genes strongly correlated with HD and was enriched in transport-related genes. Bioinformatical analysis of this subnetwork highlighted CDC42, PAK1, YWHAH, NFY, DLX1, HMGN3, and PRMT3. Moreover, we found that CREB1 can regulate 78.0% of genes whose mRNA levels correlated with HD in the blood of patients. Alterations in protein transport, metabolism, transcriptional regulation, and CDC42-mediated functions are likely central features of HD. Further our data substantiate the role of transcriptional regulators that have not been reported in the context of HD (e.g. DLX1, HMGN3 and PRMT3) and strongly suggest dysregulation of NFY and its target genes across tissues. A large proportion of the identified genes such as CDC42 were also altered in Parkinson’s (PD) and Alzheimer’s disease (AD). The observed dysregulation of CDC42 and YWHAH in samples from HD, AD and PD patients indicates that those genes and their upstream regulators may be interesting therapeutic targets.

The Zinc-BED transcription factor Bedwarfed promotes proportional dendritic growth and branching through transcriptional and translational regulation inDrosophila

“…Position-Specific Iterated BLAST (PSI-BLAST) analysis of Bdwf protein sequence revealed that Bdwf shares sequence similarities with MSANTD4 and Zbed4 in mouse and ZBED4 in humans. While MSANTD4 has been linked to Huntington’s disease, and recent studies have linked ZBED4 to schizophrenia and Phelan-McDermid syndrome, little is known about the underlying mechanism of these proteins (Nyegaard et al ., 2010; Mitz et al ., 2018; Schenkel et al ., 2021; Seefelder and Kochanek, 2021). Our study may provide new and valuable entry-points for further research on the role of these proteins in the nervous system function and dysfunction.…”

Relation of CDC42, Th1, Th2, and Th17 cells with cognitive function decline in Alzheimer's disease

“… 25 , 26 Based on these findings, the CDC42 dysregulation and its clinical value in serving as a biomarker for the neurodegenerative disease have been explored in recent studies. 27 , 28 , 29 , 30 For, instance, one study exhibits that the CDC42 is overexpressed in Huntington's disease patients. 27 Another study discloses that CDC42 serves as a differentially expressed RNA in AD patients by bioinformatics analysis from the GSE48350 data.…”

“… 27 , 28 , 29 , 30 For, instance, one study exhibits that the CDC42 is overexpressed in Huntington's disease patients. 27 Another study discloses that CDC42 serves as a differentially expressed RNA in AD patients by bioinformatics analysis from the GSE48350 data. 28 However, the study about detecting CDC42 expression in AD patients is rarely reported.…”

“…CDC42 belongs to the Rho GTPase family which is closely involved in regulating the morphogenesis and remodeling of actin‐based neuronal structures 25,26 . Based on these findings, the CDC42 dysregulation and its clinical value in serving as a biomarker for the neurodegenerative disease have been explored in recent studies 27–30 . For, instance, one study exhibits that the CDC42 is overexpressed in Huntington's disease patients 27 .…”

Current Diagnostic Methods and Non-Coding RNAs as Possible Biomarkers in Huntington’s Disease

“…RNA metabolism dysregulation is a common feature of most neurodegenerative diseases [ 51 ]. Accordingly, dysregulated gene expression in HD patients’ brain samples or in in vivo and in in vitro models, has been described, exploiting different genome-wide techniques [ 52 , 53 , 54 , 55 , 56 , 57 ]. Alteration in RNA expression and processing might be identifiable from the very early stages of the disease, when neurons might be still viable, although not properly functional.…”