Gene co-expression networks shed light into diseases of brain iron accumulation.
Gene co-expression networks shed light into diseases of brain iron accumulation.
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DOI：
10.1016/j.nbd.2015.12.004
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发表时间：
2016-03
影响因子：
6.1
通讯作者：
Houlden H
中科院分区：
文献类型：
--
作者：
Bettencourt C;Forabosco P;Wiethoff S;Heidari M;Johnstone DM;Botía JA;Collingwood JF;Hardy J;UK Brain Expression Consortium (UKBEC);Milward EA;Ryten M;Houlden H
在常见和罕见的神经退行性疾病中均观察到异常脑铁沉积，包括归类为伴脑铁蓄积的神经退行性疾病（NBIA），其特征在于基底神经节中的局灶性铁蓄积。两个NBIA基因直接参与铁代谢，但其他NBIA相关基因是否也调节人类大脑中的铁稳态，以及异常铁沉积是否有助于神经退行性过程仍在很大程度上未知。本研究旨在扩大我们对这些铁超载疾病的理解，并通过使用系统生物学方法确定已知NBIA基因及其主要相互作用伙伴之间的关系。我们使用了来自101个神经病理正常个体（10个大脑区域）的人脑样本的全转录组基因表达数据，以生成加权基因共表达网络，并以无监督的方式对10个已知的NBIA基因进行聚类。我们研究了NBIA富集网络的相关细胞类型和途径，以及它们是否被NBIA患病组织和体内小鼠模型中的铁负荷破坏。我们确定了两个基底神经节基因共表达模块显着富集NBIA基因，这类似于神经元和少突胶质细胞的签名。这些NBIA基因网络富含铁相关基因，并涉及突触和脂质代谢相关途径。我们的数据还表明，这些网络被过量的脑铁负荷所破坏。我们确定了NBIA疾病起源中的多种细胞类型。我们还发现了NBIA网络和铁相关过程之间的不可预见的联系，并证明了NBIA和表型重叠疾病之间的会聚途径。我们的研究结果通过提供新的致病基因和治疗干预的可能点，对这些疾病具有进一步的相关性。加权基因共表达分析提供了对脑疾病生物学的见解。过量的脑铁超载破坏正常的基底神经节基因网络。基底神经节铁蓄积可能决定疾病进展。
Aberrant brain iron deposition is observed in both common and rare neurodegenerative disorders, including those categorized as Neurodegeneration with Brain Iron Accumulation (NBIA), which are characterized by focal iron accumulation in the basal ganglia. Two NBIA genes are directly involved in iron metabolism, but whether other NBIA-related genes also regulate iron homeostasis in the human brain, and whether aberrant iron deposition contributes to neurodegenerative processes remains largely unknown. This study aims to expand our understanding of these iron overload diseases and identify relationships between known NBIA genes and their main interacting partners by using a systems biology approach. We used whole-transcriptome gene expression data from human brain samples originating from 101 neuropathologically normal individuals (10 brain regions) to generate weighted gene co-expression networks and cluster the 10 known NBIA genes in an unsupervised manner. We investigated NBIA-enriched networks for relevant cell types and pathways, and whether they are disrupted by iron loading in NBIA diseased tissue and in an in vivo mouse model. We identified two basal ganglia gene co-expression modules significantly enriched for NBIA genes, which resemble neuronal and oligodendrocytic signatures. These NBIA gene networks are enriched for iron-related genes, and implicate synapse and lipid metabolism related pathways. Our data also indicates that these networks are disrupted by excessive brain iron loading. We identified multiple cell types in the origin of NBIA disorders. We also found unforeseen links between NBIA networks and iron-related processes, and demonstrate convergent pathways connecting NBIAs and phenotypically overlapping diseases. Our results are of further relevance for these diseases by providing candidates for new causative genes and possible points for therapeutic intervention. Weighted gene co-expression analysis gives insights on brain disease biology. Excessive brain iron overload disrupts normal basal ganglia gene networks. Basal ganglia iron accumulation may determine disease progression.