期刊
GENES
卷 13, 期 12, 页码 -出版社
MDPI
DOI: 10.3390/genes13122385
关键词
Huntington's disease; Brodmann Area 9; tissue-specific network analysis; variant effect; function interaction network
Huntington's disease is a neurodegenerative disorder characterized by the vulnerability of striatal projection neurons. Variants in gene expression and miRNA binding are found to affect the regulatory functions, disrupt transcription factor networks, and contribute to abnormal neuroinflammation. Furthermore, mitochondrial dysfunction, neuroinflammation, and disrupted vasculature play a role in blood-brain barrier dysfunction and abnormal energy metabolism. Restoring blood-brain barrier functionality and energy metabolism may be potential therapeutic strategies for protecting neurons in Huntington's disease.
Huntington's disease (HD) is a neurodegenerative disorder with autosomal dominant inheritance caused by glutamine expansion in the Huntingtin gene (HTT). Striatal projection neurons (SPNs) in HD are more vulnerable to cell death. The executive striatal population is directly connected with the Brodmann Area (BA9), which is mainly involved in motor functions. Analyzing the disease samples from BA9 from the SRA database provides insights related to neuron degeneration, which helps to identify a promising therapeutic strategy. Most gene expression studies examine the changes in expression and associated biological functions. In this study, we elucidate the relationship between variants and their effect on gene/downstream transcript expression. We computed gene and transcript abundance and identified variants from RNA-seq data using various pipelines. We predicted the effect of genome-wide association studies (GWAS)/novel variants on regulatory functions. We found that many variants affect the histone acetylation pattern in HD, thereby perturbing the transcription factor networks. Interestingly, some variants affect miRNA binding as well as their downstream gene expression. Tissue-specific network analysis showed that mitochondrial, neuroinflammation, vasculature, and angiogenesis-related genes are disrupted in HD. From this integrative omics analysis, we propose that abnormal neuroinflammation acts as a two-edged sword that indirectly affects the vasculature and associated energy metabolism. Rehabilitation of blood-brain barrier functionality and energy metabolism may secure the neuron from cell death.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据