Genes Implicated in Familial Parkinson's Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage.
Genes Implicated in Familial Parkinson's Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage.
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Genes Implicated in Familial Parkinson's Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage.
DOI：
10.3390/ijms22094643
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发表时间：
2021-04-28
影响因子：
5.6
通讯作者：
Reyes-Resina I
中科院分区：
文献类型：
--
作者：
Franco R;Rivas-Santisteban R;Navarro G;Pinna A;Reyes-Resina I
帕金森病（PD）中黑质多巴胺能神经元变性的机制尚不清楚。该疾病的病理特征之一是α-突触核蛋白（α-syn）沉积，其发生在家族性和散发性PD患者的脑中。本文构成了一个叙述性的审查，利用相关的基因（SNCA，LRRK 2，GBA，UCHL 1，VPS 35，PRKN，PINK 1，ATP 13 A2，PLA 2G 6，DNAJC 6，SYNJ 1，DJ-1/PARK 7和FBXO 7）参与帕金森氏病（PD）的家族性病例的信息，以探讨其在破译多巴胺能神经支配的起源在许多类型的PD的有用性。使用检索相互作用基因/蛋白质（STRING）数据库的搜索工具评价基因或基因产物之间的直接或功能性相互作用。其基本原理是提出SNCA（编码在PD中聚集的α-syn的基因）与其他基因（其突变导致早发性PD）之间相互作用的图谱。该图谱与使用动物模型获得的结果形成对比，这些动物模型是其中一个基因的敲除或表达突变的人类基因。通过将基于STRING的测定的计算机数据与转基因动物的体外和体内数据相结合，出现了两种可能的机制：（i）天然α-syn的加工由于参与囊泡运输和蛋白质加工的基因突变而改变，或（ii）α-syn突变体改变了正确囊泡运输和蛋白质加工所必需的机制。线粒体是一个共同点，因为这两种机制都需要额外的能量产生，而神经元存活所需的能量主要来自葡萄糖的完全氧化。多巴胺本身可导致多巴胺能神经元的线粒体的额外负担，因为其处理产生自由基。作用于神经元线粒体中G蛋白偶联受体（GPCR）的药物可能最终靶向这些受体，以减少氧化负荷并提高线粒体性能。总之，家族性PD相关基因数据的分析提供了散发病例病因学的相关信息，并可能提出新的治疗方法。
The mechanism of nigral dopaminergic neuronal degeneration in Parkinson’s disease (PD) is unknown. One of the pathological characteristics of the disease is the deposition of α-synuclein (α-syn) that occurs in the brain from both familial and sporadic PD patients. This paper constitutes a narrative review that takes advantage of information related to genes (SNCA, LRRK2, GBA, UCHL1, VPS35, PRKN, PINK1, ATP13A2, PLA2G6, DNAJC6, SYNJ1, DJ-1/PARK7 and FBXO7) involved in familial cases of Parkinson’s disease (PD) to explore their usefulness in deciphering the origin of dopaminergic denervation in many types of PD. Direct or functional interactions between genes or gene products are evaluated using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The rationale is to propose a map of the interactions between SNCA, the gene encoding for α-syn that aggregates in PD, and other genes, the mutations of which lead to early-onset PD. The map contrasts with the findings obtained using animal models that are the knockout of one of those genes or that express the mutated human gene. From combining in silico data from STRING-based assays with in vitro and in vivo data in transgenic animals, two likely mechanisms appeared: (i) the processing of native α-syn is altered due to the mutation of genes involved in vesicular trafficking and protein processing, or (ii) α-syn mutants alter the mechanisms necessary for the correct vesicular trafficking and protein processing. Mitochondria are a common denominator since both mechanisms require extra energy production, and the energy for the survival of neurons is obtained mainly from the complete oxidation of glucose. Dopamine itself can result in an additional burden to the mitochondria of dopaminergic neurons because its handling produces free radicals. Drugs acting on G protein-coupled receptors (GPCRs) in the mitochondria of neurons may hopefully end up targeting those receptors to reduce oxidative burden and increase mitochondrial performance. In summary, the analysis of the data of genes related to familial PD provides relevant information on the etiology of sporadic cases and might suggest new therapeutic approaches.
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影响因子：
10.4
作者：
Bronstein, Jeff;Carvey, Paul;Chen, Honglei;Cory-Slechta, Deborah;DiMonte, Donato;Duda, John;English, Paul;Goldman, Samuel;Grate, Stephen;Hansen, Johnni;Hoppin, Jane;Jewell, Sarah;Kamel, Freya;Koroshetz, Walter;Langston, James W.;Logroscino, Giancarlo;Nelson, Lorene;Ravina, Bernard;Rocca, Walter;Ross, George W.;Schettler, Ted;Schwarzschild, Michael;Scott, Bill;Seegal, Richard;Singleton, Andrew;Steenland, Kyle;Tanner, Caroline M.;Van Den Eeden, Stephen;Weisskopf, Marc
通讯作者：
Weisskopf, Marc
DOI：
10.1083/jcb.201401070
发表时间：
2014-09-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ashrafi G;Schlehe JS;LaVoie MJ;Schwarz TL
通讯作者：
Schwarz TL
影响因子：
5.3
作者：
Berthet, Amandine;Bezard, Erwan;Martin-Negrier, Marie-Laure
通讯作者：
Martin-Negrier, Marie-Laure
影响因子：
5.4
作者：
Beatman, Erica L.;Massey, Aaron;Beckham, J. David
通讯作者：
Beckham, J. David
影响因子：
5.9
作者：
Arle, JE;Alterman, RL
通讯作者：
Alterman, RL