探索腦衍生神經滋養因子之特徵及其在情緒疾患中所扮演的角色

背景：在眾多解釋情感性疾患的病理機制中，神經滋養因子假說(neurotrophic hypothesis)是近年來相當被重視的一個論點，其中最常被大家所研究的是腦衍生神經滋養因子(brain-derived neurotrophic factor, BDNF)，它在生物學中所扮演的角色通常被認為和神經元的存活和分化有關。然而，截至目前為止，有關腦衍生神經滋養因子在情感性疾患中的特徵以及背後的機制都還不是那麼明確，而先前許多研究顯示了腦衍生神經滋養因子與情感性疾患之間的關係，在不同的研究設計下是不一致的。目的：這個研究希望可以利用系統生物學的方法，包含了分子演化、基因體研究、蛋白質的功能及生物路徑的分析，來探索腦衍生神經滋養因子在情感性疾患中所扮演的角色。方法：在分子演化的部分，我們利用了一些現有的套件軟體來幫我們檢視十二個物種之間序列的相似性、多重序列比對、演化樹的建立以及是否有經歷正向天擇 (positive selection)。基因體的研究以及了解蛋白質的功能與角色則是利用文獻回顧的方式，整理過往在這兩方面的發展跟研究進行統整。最後在生物路徑分析的部分，我們利用一些較知名且整合型的資料庫，選擇與腦衍生神經滋養因子有交互作用的蛋白及其對應的生物路徑，利用現有的全基因體相關性基因型(GWAS)的資料來進行與情緒障礙間相關性的路徑分析。結果：在各個物種間序列比對的結果顯示，腦衍生神經滋養因子是一個高度保守的基因，在脊索動物和人類的序列上有百分之七十五的相似度，而在脊椎動物上相似度更可高達百分之八十五點九甚至是百分之百。在分子演化方面的分析則是發現在這十二個物種之間沒有經歷過正向天擇。文獻回顧和統合分析顯示了不管是在什麼樣的基因體研究設計上，像是連鎖分析研究、相關性研究、基因表現或是全基因體相關性研究中，腦衍生神經滋養因子在情感性疾患上的關係都得到不一致的結果。成熟的腦衍生神經滋養因子是從該因子的前驅物產生而來的，而這兩種蛋白扮演了相反的生物功能。研究顯示，腦衍生神經滋養因子的前驅物會對壓力刺激有所反應，而且跟認知功能有所相關，意味著腦衍生神經滋養因子以及其前驅物在情感性疾患上都是有必要進一步研究的。在生物路徑分析方面，我們指認出了和腦衍生神經滋養因子有交互作用的蛋白，並且將轉譯出這些蛋白的基因對到情感性疾患的全基因體相關性資料中。在這個分析中，我們指出了一些可能參與了情感性疾患機制的生物路徑。結論：由於生物機制的複雜性以及單一研究設計的限制性，利用系統性的方式來檢視腦衍生神經滋養因子所扮演的特徵可以提供更多的機會，了解其在情感性疾患中背後所參與的病理機制。

關鍵字

腦衍生神經滋養因子；情感性疾患；憂鬱症；躁鬱症；神經滋養因子假說；系統生物學

並列摘要

Background: The neurotrophic hypothesis for mood disorders has been proposed over a decade. Brain-derived neurotrophic factor (BDNF) is one of the most studied, which plays an important role in neuronal survival and differentiation. However, the features and underlying mechanisms of BDNF for mood disorders is yet clear. Previous studies using different designs often reported inconsistent results for the relationship between BDNF and mood disorders. Objects: This study aims to explore the features of BDNF for its role in mood disorders by using the viewpoint of systems biology, including aspects in molecular evolution, genomic studies, protein functions, and pathway analysis. Methods: In molecular evolution, we used existed software to conduct sequence examination, multiple alignments, phylogenetic trees and positive selection across 12 species and several human populations. Literature review was used to summarize results from previous genomic studies of BDNF and functions of pro-BDNF and mature-BDNF. We choose proteins that interact with BDNF and pathways from well-known integrated databases. The genome-wide association data for mood disorders were used to conduct pathway analysis. Results: Results of sequence alignment among different species revealed that BDNF is a highly conserved gene, having 75% identity in chordates with human and 85.9%-100% in vertebrates. Molecular evolutionary analysis found no signs of recent positive selection. Literature review and meta-analysis found inconsistent relationship between BDNF and mood disorders in different designs, such as linkage, association, gene expression, or GWA studies. Mature BDNF was produced from pro-BDNF and the two proteins have opposite biological functions. Studies suggested that pro-BDNF may response to stress and correlate with cognition, implicating the necessity to study both pro- and m-BDNF for mood disorders. We identified proteins that interact with BDNF (I-Genes) and mapped these genes to genome-wide association datasets of mood disorders. Pathway analyses identified possible biological pathways that involved with BDNF or I-Genes for mood disorders. Conclusions: Due to the complexity of biological processes involve in mood disorders, examining the features of BDNF systematically would provide opportunities to have a better understanding for the mechanisms underlying mood disorders.

並列關鍵字

Brain-derived neurotrophic factor ； mood disorders ； major depression disorder ； bipolar disorder ； neurotrophic hypothesis ； systems biology

參考文獻

Barker, P. A. (2009). Whither proBDNF? Nat Neurosci, 12(2), 105-106. doi: 10.1038/nn0209-105

Barnes, P., & Thomas, K. L. (2008). Proteolysis of proBDNF Is a Key Regulator in the Formation of Memory. PLoS One, 3(9), e3248. doi: 10.1371/journal.pone.0003248

Barnett, J. H., & Smoller, J. W. (2009). The genetics of bipolar disorder. [Review]. Neuroscience, 164(1), 331-343. doi: 10.1016/j.neuroscience.2009.03.080

Binder, D. K., & Scharfman, H. E. (2004). Brain-derived neurotrophic factor. [Review]. Growth Factors, 22(3), 123-131.

Brunoni, A. R., Lopes, M., & Fregni, F. (2008). A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol, 11(8), 1169-1180. doi: 10.1017/s1461145708009309

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探索腦衍生神經滋養因子之特徵及其在情緒疾患中所扮演的角色

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