Is the Enzyme ACMSD a Novel Therapeutic Target in Parkinson's Disease?
Is the Enzyme ACMSD a Novel Therapeutic Target in Parkinson's Disease?
复制标题
DOI：
10.3233/jpd-171240
复制
发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Brundin L
中科院分区：
文献类型：
--
作者：
Thirtamara-Rajamani K;Li P;Escobar Galvis ML;Labrie V;Brundin P;Brundin L
几个大的全基因组关联研究已经确定了一个基因座，该基因座与编码氨基羧基粘康酸半醛脱羧酶（ACMSD）的基因非常接近，与帕金森病（PD）的风险相关，初步表明这种酶可能影响PD的发病机制。进一步支持这一点来自最近鉴定的疾病隔离终止密码子突变ACMSD在一个家庭与帕金森氏症，和错义突变ACMSD基因预测破坏酶的功能，在一个典型的PD个体。ACMSD是犬尿氨酸途径的一部分，负责色氨酸催化分解为NAD+，在此过程中产生几种神经活性代谢物。该酶位于该途径的关键分支点，限制具有兴奋毒性和炎症特性的神经毒素喹啉酸的产生。在这篇综述中，我们讨论了ACMSD的功能及其在PD发病机制中的潜在参与的遗传研究结果。
Several large genome wide association studies have identified a locus in close proximity to the gene encoding the enzyme aminocarboxymuconate-semialdehyde-decarboxylase (ACMSD) to be associated with the risk for Parkinson’s disease (PD), tentatively suggesting that this enzyme might influence PD pathogenesis. Further support for this comes from the recent identification of a disease-segregating stop codon mutation in ACMSD in a family with Parkinsonism, and a missense mutation in the ACMSD gene predicted to disrupt enzyme function in an individual with typical PD. ACMSD is part of the kynurenine pathway, responsible for the catalytic breakdown of tryptophan into NAD+, generating several neuroactive metabolites in the process. The enzyme is located at a key branch-point of the pathway, limiting the production of the neurotoxin quinolinic acid, which has excitotoxic and inflammatory properties. In this review, we discuss the genetic findings in light of the functions of ACMSD and its potential involvement in PD pathogenesis.