Regulatory network underlying alterations of gene expression in early death of Huntington's disease

Abstract

The aim of this study is to explore the genomic mechanism of early death in Huntington’s disease (HD). We identified 10160 and 1511 differentially expressed genes (DEGs) from comparisons of HD versus control and early versus late death, respectively. On the basis of 922 overlapped DEGs among them, six functional modules were established by weight gene correlation network analysis. The turquoise module most strongly related to overall survival of HD was significantly enriched in GABAergic synapse, retrograde endocannabinoid signaling and neuroactive ligand-receptor interaction. Low expression of five DEGs (CA10, WSB2, ACTR3B, PCDH19 and GABRB3) with highest degree of connectivity and non-zero regression coefficients were identified as hub genes, based on which the LASSO model exactly predicted the occurrence of early death in HD. Furthermore, the network analysis revealed indirect interaction of CA10 with the central hub gene GABRB3, which was involved in the pathway of GABAergic synapse. Compared with high expression of hub genes, their low expression appeared shorter overall survival of HD patients according to Kaplan-Meier survival analysis. Consequently, low expression of CA10, WSB2, ACTR3B, PCDH19 and GABRB3 were possibly associated with early death of HD. The likelihood of low expression of GABRB3 regulated by CA10 in GABAergic synapse contributed to the pathogenesis of early death in HD.

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“…The GNB5 which encodes the beta 5 subunit of heterotrimeric G proteins, is predominantly expressed in the nervous system and is essential for natural brain development [ 36 , 37 ]. One study showed that GNB5 is a hub gene in Huntington's disease (HD) [ 38 ]. Utpala et al demonstrated that GNB5 is one of the 10 most significant hub genes involved in GABAergic synapse, Retrograde endocannabinoid signaling, and Ras signaling pathways in AD (Alzheimer disease) [ 39 ].…”