Huang Miaozhen, de Koning Tom J, Tijssen Marina A J, Verbeek Dineke S
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Pediatrics, Department of Clinical Sciences, Lund University, Sweden.
Biochim Biophys Acta Mol Basis Dis. 2021 Jan 1;1867(1):165976. doi: 10.1016/j.bbadis.2020.165976. Epub 2020 Oct 2.
There is growing evidence that the neuropsychiatric and neurological disorders depression, ataxia and dystonia share common biological pathways. We therefore aimed to increase our understanding of their shared pathophysiology by investigating their shared biological pathways and molecular networks.
We constructed gene sets for depression, ataxia, and dystonia using the Human Phenotype Ontology database and genome-wide association studies, and identified shared genes between the three diseases. We then assessed shared genes in terms of functional enrichment, pathway analysis, molecular connectivity, expression profiles and brain-tissue-specific gene co-expression networks.
The 33 genes shared by depression, ataxia and dystonia are enriched in shared biological pathways and connected through molecular complexes in protein-protein interaction networks. Biological processes common/shared to all three diseases were identified across different brain tissues, highlighting roles for synaptic transmission, synaptic plasticity and nervous system development. The average expression of shared genes was significantly higher in the cerebellum compared to other brain regions, suggesting these genes have distinct cerebellar functions. Several shared genes also showed high expression in the cerebellum during prenatal stages, pointing to a functional role during development.
The shared pathophysiology of depression, ataxia and dystonia seems to converge onto the cerebellum that maybe particularly vulnerable to changes in synaptic transmission, regulation of synaptic plasticity and nervous system development. Consequently, in addition to regulating motor coordination and motor function, the cerebellum may likely play a role in mood processing.
越来越多的证据表明，神经精神疾病和神经系统疾病中的抑郁症、共济失调和肌张力障碍共享共同的生物学途径。因此，我们旨在通过研究它们共享的生物学途径和分子网络来加深对其共同病理生理学的理解。
我们使用人类表型本体数据库和全基因组关联研究构建了抑郁症、共济失调和肌张力障碍的基因集，并确定了这三种疾病之间的共享基因。然后，我们从功能富集、途径分析、分子连通性、表达谱和脑组织特异性基因共表达网络等方面评估了共享基因。
抑郁症、共济失调和肌张力障碍共享的33个基因在共享的生物学途径中富集，并通过蛋白质-蛋白质相互作用网络中的分子复合物相互连接。在不同的脑组织中鉴定出了这三种疾病共同的生物学过程，突出了突触传递、突触可塑性和神经系统发育的作用。与其他脑区相比，共享基因在小脑中的平均表达显著更高，表明这些基因具有独特的小脑功能。一些共享基因在产前阶段的小脑中也表现出高表达，表明其在发育过程中的功能作用。
抑郁症、共济失调和肌张力障碍的共同病理生理学似乎集中在小脑上，小脑可能特别容易受到突触传递变化、突触可塑性调节和神经系统发育的影响。因此，除了调节运动协调和运动功能外，小脑可能还在情绪处理中发挥作用。
