The genetic architecture of mitochondrial dysfunction in Parkinson's disease.
The genetic architecture of mitochondrial dysfunction in Parkinson's disease.
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DOI：
10.1007/s00441-017-2768-8
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发表时间：
2018-07
影响因子：
3.6
通讯作者：
Krüger R
中科院分区：
文献类型：
--
作者：
Larsen SB;Hanss Z;Krüger R
线粒体损伤是与帕金森病（PD）有关的一个公认的病理途径。散发性帕金森病患者死后的大脑中发现了线粒体呼吸链复合体I的缺陷。此外，一些疾病相关基因与线粒体通路相关，如PRKN、PINK1、DJ-1和HTRA2，并与线粒体损伤相关。这种表型可能是由线粒体质量控制机制在不同水平上的功能障碍引起的：分子、细胞器或细胞。线粒体未折叠蛋白反应代表分子水平，涉及多种伴侣蛋白和蛋白酶。如果分子水平的质量控制不够，则需要细胞器水平的质量控制，并涉及线粒体自噬和线粒体衍生的囊泡，以隔离整个或部分功能失调的细胞器。只有当损伤太严重时，它才会通过细胞凋亡导致细胞死亡，细胞凋亡定义了细胞水平的质量控制。在这里，我们回顾了目前已知的pd相关遗传变异如何干扰不同水平的线粒体质量控制。我们讨论了最近发现的PARK位点（PARK 17-23）和GBA、LRRK2和SNCA的一些易感性变异的分级风险概念。最后，PD候选基因（如HSPA9、TRAP1和RHOT1）中罕见遗传变异的新概念，完善了PD复杂遗传结构的图景，这将指导未来的精准医学方法。
Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson’s disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post-mortem brains from sporadic PD patients. Furthermore, several disease-related genes are linked to mitochondrial pathways, such as PRKN, PINK1, DJ-1 and HTRA2 and are associated with mitochondrial impairment. This phenotype can be caused by the dysfunction of mitochondrial quality control machinery at different levels: molecular, organellar or cellular. Mitochondrial unfolded protein response represents the molecular level and implicates various chaperones and proteases. If the molecular level of quality control is not sufficient, the organellar level is required and involves mitophagy and mitochondrial-derived vesicles to sequester whole dysfunctional organelle or parts of it. Only when the impairment is too severe, does it lead to cell death via apoptosis, which defines the cellular level of quality control. Here, we review how currently known PD-linked genetic variants interfere with different levels of mitochondrial quality control. We discuss the graded risk concept of the most recently identified PARK loci (PARK 17–23) and some susceptibility variants in GBA, LRRK2 and SNCA. Finally, the emerging concept of rare genetic variants in candidates genes for PD, such as HSPA9, TRAP1 and RHOT1, complete the picture of the complex genetic architecture of PD that will direct future precision medicine approaches.
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DOI：
10.2174/1874205x01206010001
发表时间：
2012
期刊：
The open neurology journal
影响因子：
--
作者：
Anvret A;Ran C;Westerlund M;Sydow O;Willows T;Olson L;Galter D;Belin AC
通讯作者：
Belin AC
影响因子：
9
作者：
通讯作者：
--
影响因子：
56.9
作者：
Bonifati, V;Rizzu, P;Heutink, P
通讯作者：
Heutink, P
影响因子：
9.8
作者：
Chartier-Harlin, Marie-Christine;Dachsel, Justus C.;Farrer, Matthew J.
通讯作者：
Farrer, Matthew J.
影响因子：
9.9
作者：
Anheim, M.;Elbaz, A.;Brice, A.
通讯作者：
Brice, A.