Eisenberg Daniel P, Kohn Philip D, Hegarty Catherine E, Ianni Angela M, Kolachana Bhaskar, Gregory Michael D, Masdeu Joseph C, Berman Karen F
Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, NIH, DHHS, Bethesda, MD, USA.
Neuropsychopharmacology. 2016 Aug;41(9):2303-8. doi: 10.1038/npp.2016.31. Epub 2016 Feb 29.
The synthesis of multiple amine neurotransmitters, such as dopamine, norepinephrine, serotonin, and trace amines, relies in part on DOPA decarboxylase (DDC, AADC), an enzyme that is required for normative neural operations. Because rare, loss-of-function mutations in the DDC gene result in severe enzymatic deficiency and devastating autonomic, motor, and cognitive impairment, DDC common genetic polymorphisms have been proposed as a source of more moderate, but clinically important, alterations in DDC function that may contribute to risk, course, or treatment response in complex, heritable neuropsychiatric illnesses. However, a direct link between common genetic variation in DDC and DDC activity in the living human brain has never been established. We therefore tested for this association by conducting extensive genotyping across the DDC gene in a large cohort of 120 healthy individuals, for whom DDC activity was then quantified with [(18)F]-FDOPA positron emission tomography (PET). The specific uptake constant, Ki, a measure of DDC activity, was estimated for striatal regions of interest and found to be predicted by one of five tested haplotypes, particularly in the ventral striatum. These data provide evidence for cis-acting, functional common polymorphisms in the DDC gene and support future work to determine whether such variation might meaningfully contribute to DDC-mediated neural processes relevant to neuropsychiatric illness and treatment.
多种胺类神经递质的合成，如多巴胺、去甲肾上腺素、血清素和痕量胺，部分依赖于多巴脱羧酶（DDC，AADC），该酶是正常神经活动所必需的。由于DDC基因中罕见的功能丧失突变会导致严重的酶缺乏以及严重的自主神经、运动和认知障碍，因此有人提出，DDC常见的基因多态性是导致DDC功能发生更适度但临床上重要改变的一个原因，这些改变可能会影响复杂的遗传性神经精神疾病的风险、病程或治疗反应。然而，DDC常见基因变异与活人脑中DDC活性之间的直接联系从未得到证实。因此，我们通过对120名健康个体组成的大型队列中的DDC基因进行广泛基因分型来测试这种关联，随后用[（18）F] - FDOPA正电子发射断层扫描（PET）对这些个体的DDC活性进行定量。对感兴趣的纹状体区域估计了特定摄取常数Ki（一种衡量DDC活性的指标），发现它可由五个测试单倍型之一预测，尤其是在腹侧纹状体中。这些数据为DDC基因中的顺式作用功能性常见多态性提供了证据，并支持未来开展工作，以确定这种变异是否可能对与神经精神疾病及治疗相关的DDC介导的神经过程有意义地做出贡献。
