精神分裂症患者AKT1基因型、淋巴球AKT1蛋白質表現量、與神經心理功能缺損的相關性研究

The Association Study of AKT1 Genotype, Lymphocyte AKT1 Expression Level, and Neuropsychological Performance Deficit in Schizophrenic Patients

李明儀(Ming-Yih Lee)

指導教授 ： 胡海國

國立臺灣大學/醫學院/臨床醫學研究所/碩士(2007年)

https://doi.org/10.6342/NTU.2007.00317

摘要

精神分裂症是一重大慢性的神經精神疾病，其病理生理機轉目前仍不清楚。自從Emamian等人(2004)報告多方面的證據聚焦於精神分裂症AKT1- GSK3β的訊息傳導有缺損之後，出現了許多相關的研究探討這樣的推論。然而，精神分裂症患者是一群異質性很高的族群，我們因此好奇究竟是哪一群精神分裂症患者會表現有AKT1蛋白質功能的缺損？或者說這樣的缺損的究竟和患者的哪些臨床表現相關？有許多試管內(in vitro)的實驗提到AKT1蛋白質與神經細胞內的訊息傳遞、神經傳導、或神經發育過程有所相關；另外也有動物實驗支持AKT1- GSK3β的訊息傳導缺損會導致工作記憶(working memory)表現缺損。目前已知精神分裂症患者除了有複雜多樣的臨床精神症狀外，也會有神經心理功能中注意力(attention)及工作記憶(working memory)功能的缺損。我們因此合理的假設AKT1蛋白質的功能缺損可能與精神分裂症的持續注意力及工作記憶功能的缺損有相關。
本研究有幾個主要的目的：(1)探討AKT1蛋白質在EBV轉型淋巴球的表現量的降低，是否發生於精神分裂症患者身上；(2)究竟是哪一群患者會表現出這種現象？(3)探討AKT1基因的單套基因型(haplotype) 是否與EBV轉型淋巴球的AKT1蛋白質表現量有相關；(4)探討精神分裂症患者EBV轉型淋巴球的AKT1蛋白質功能缺損是否與其持續注意力測驗(Continuous Performance Test)及工作記憶表現有相關。
本計畫共收集95位精神分裂症患者，及62位正常對照個案。先定出這些個案AKT1基因的六個單核苷酸多型性(single nucleotide polymorphism, SNP)的基因型。以ELISA方法測量EBV轉型淋巴球AKT1蛋白質的量。使用持續注意力測驗(Continuous Performance Test)評估個案的持續注意力功能；使用魏氏智力測驗(WAIS-R)的語言智商分測驗(VIQ subtest)中的各分項目評估個案的工作記憶功能。使用SAPS(the Scale for the Assessment of Positive Symptoms)和SANS(the Scale for the Assessment of Negative Symptoms)問卷中文版評估患者精神症狀嚴重程度。
研究結果發現精神分裂症病患EBV轉型淋巴球的AKT1蛋白質的表現量顯著較正常對照組為低。如果將精神分裂症病患區分為來自單發性家庭(一個兩代家庭中只有一個人生病, simplex family)及多發性家庭(一個兩代家庭有兩個或以上的兄弟姊妹生病, multiplex family)兩組，則發現來自多發性家庭的病患AKT1蛋白質表現量顯著較來自單發性家庭的病患及正常對照組為低。AKT1蛋白質表現量與患者的精神症狀嚴重程度無關。AKT1基因的六個單核苷酸變異與其AKT1蛋白質表現量無關。AKT1蛋白質量與持續注意力測驗結果無顯著相關，但與魏氏智力測驗中的逆行數字廣度測驗結果成正相關 ( r= 0.283 )，達統計上的顯著程度 (p= 0.004)。
本研究結論為精神分裂症患者EBV轉型淋巴球的AKT1蛋白質的表現量顯著較正常對照組為低。這樣的表現與精神症狀無關；但與其遺傳負荷(genetic loading)有關；遺傳負荷越高者，其表現量越低。目前沒有證據支持AKT1蛋白質表現量與持續注意力表現有相關。 但AKT1蛋白質表現量與魏氏智力測驗中的逆行數字廣度測驗結果有顯著正相關，與我們原先的假設相符，意即AKT1蛋白質與工作記憶表現相關。AKT1蛋白質表現量與AKT1基因型無關。因此我們推論精神分裂症患者EBV轉型淋巴球的AKT1蛋白質量降低可能並不是AKT1基因的直接影響，而是因為與AKT1蛋白質路徑相關的其他分子改變，所引發的次級變化。

關鍵字

精神分裂症 ； AKT1基因 ； 持續注意力測驗 ； 工作記憶

並列摘要

Schizophrenia is a devastating neuropsychiatric disorder. The pathophysiological mechanism is still unknown. The study of Emamian et al. (2004) got a fruitful achievement and established the hypothesis that the AKT1- GSK3β signaling pathway was possibly involved in the pathogenesis of schizophrenia. However, there left questions unanswered: which characteristics of schizophrenia are related to AKT1 protein function impairment? In animal models, AKT1 plays crucial role in working memory formation. Individuals with schizophrenia also show performance deficits on a wide range of working memory tasks. We hypothesize that the AKT1 protein function is associated with the sustained attention/ working memory performance deficit of schizophrenia patients.
This study aims to answer the following questions: (1) to see if schizophrenia patients have lower AKT1 protein level in EBV- transformed lymphocytes; (2) to find out which subgroup of schizophrenia patients have lower level of AKT1 protein; (3) to see if any specific risk haplotype is associated with lower AKT1 protein expression level; (4) to clarify the relationship between the AKT1 protein level and the attention/ working memory task performance.
We genotyped six SNPs of AKT1 gene on 95 schizophrenic patients and 62 normal controls and measured their AKT1 protein level of the EBV- transformed peripheral lymphocytes by ELISA. We find that schizophrenic patients have significantly lower AKT1 protein level than controls (p=0.023). The AKT1 level of the patients from the multiplex families, i.e., more than 2 affected siblings within a family, were significantly lower than that of the patients from the simplex families, i.e., only one patient within a family, and normal controls. There is no significant difference in either allele or genotype frequency of the six SNPs between patients and controls. There is no significant association between the AKT1 level and the genotypes or haplotypes. The AKT1 level is not correlated to the performance of CPT, but is significantly correlated to the performance of digit span backward repetition tasks (r= 0.283, p=0.004).
We conclude that the AKT1 protein level is related to the genetic loadings of schizophrenia. Namely, the higher genetic loading, the lower the AKT1 level. Our result failed to support the hypothesis that AKT1 level is correlated to the performance of sustained attention. Our result however support the hypothesis that the AKT1 level is correlated to working memory performance. There is no significant association between AKT1 gene and schizophrenia. The AKT1 level is not associated with the AKT1 genotypes and haplotypes. Therefore, the decrease of AKT1 level in schizophrenia may not be the direct result of AKT1 gene, but the secondary change due to alterations of other associated molecules on the AKT1 pathway.

並列關鍵字

schizophrenia ； AKT1 ； Continueous Performance Test ； Working Memory

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