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线粒体：关键细胞器帕金森病
Rubén Gómez-Sánchez
,1
何塞M.布拉沃 - 圣佩德罗,2,3,4,5,6
马修E. Gegg,7
Rosa A. González-Polo,8,9
和
José M. Fuentes8,9
1细胞生物学系，格罗宁根，格罗宁根大学医学中心，A.大学Deusinglaan 1，9713 AV荷兰格罗宁根
2Equipe 11 Labellisee par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers, 75006 Paris, France
3INSERM，U1138，75006巴黎，法国
4巴黎大学笛卡尔/巴黎V，索邦大学巴黎太阳城，75006巴黎，法国
5Üniversite电皮埃尔与玛丽·居里/巴黎第六，75006巴黎，法国
6Gustave Roussy Comprehensive Cancer Institute, 94805 Villejuif, France
7Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UK
8炫酷德Investigación生物医药恩红自我Enfermedades Neurodegenerativas（CIBERNED），西班牙
9Departamento de Bioquímica y Biología Molecular y Genética, Universidad de Extremadura, Facultad de Enfermería y Terapia Ocupacional, Avda de la Universidad S/N, 10003 Cáceres, Spain
帕金son’s disease (PD) is the second most common neurodegenerative disorder, characterized pathologically by loss of dopaminergic neurons in the黑质致密部。PD的病因仍然未知，涉及遗传和环境因素;然而，线粒体功能障碍在PD发病机制中的核心作用。在这方面，一些PD相关蛋白（PINK1，帕金，DJ-1，LRRK2和αα-突触核蛋白）链接到线粒体功能。线粒体是高度参与基本细胞功能，包括能源生产，钙稳态，氨基酸和脂质，线粒体DNA复制的代谢，和程序性细胞死亡的动态细胞器。此外，线粒体稳态紧密由几个途径，包括线粒体生物发生，重塑（融合/裂变），并通过自噬（自噬）损伤的线粒体的间隙，除其他调节。线粒体功能障碍和钙通道的自主起搏期间，参与有牵连的多巴胺能神经元的易感性增加细胞死亡的substantia nigra。
这期特刊是由2条评论和五篇文章，其中提供新的见解与可能影响PD的发病线粒体的分子和细胞通路。
In the first review (“Chaperone-Mediated Autophagy and Mitochondrial Homeostasis in Parkinson’s Disease”), the authors summarize the current knowledge about autophagy and the relevance of this degradative pathway in the maintenance of mitochondrial function. Specifically, they highlight the link between mitochondrial dysfunction and impairment of chaperone-mediated autophagy activity in PD patients.
The second review, titled “Parkinson’s Disease: The Mitochondria-Iron Link,” is focused on the relationship between accumulation of redox-active iron and the development/pathogenesis of PD. It is well-known that mitochondria are involved in the exchange of iron with the cytoplasm, with evidence suggesting that dysfunction in PD-related proteins (i.e.,α体内基因LRRK2 -核蛋白、帕金PINK1 DJ-1,,和ATP13A2) leads to iron dysregulation. Because of the neurotoxicity linked to iron accumulation, Y. Muñoz et al. suggest that iron chelation is a potential therapeutic approach to slow down the progression of the disease.
与上一次审查，包括在这个特殊问题的第一篇论文，题为“关于功能性脂类结合在ATP13A2遗址保护对线粒体和金属毒性取决于”检查ATP132A和审议的细胞保护作用的治疗靶点以减少细胞毒性。S. Martin等人。证明ATP132A需要信令脂质磷脂酸和磷脂酰肌醇3,5-二磷酸介导保护有毒的Mn2+/锌2+/Fe3+concentrations and mitochondrial stress by the toxins rotenone and MPP+。
In the second research article, “Methyl-Arginine Profile of Brain from Aged PINK1-KO+A53T-SNCA Mice Suggests Altered Mitochondrial Biogenesis,” G. Auburger et al. use a powerful experimental model (PINK1-knockout with overexpression of A53T-SNCA double-mutant mice) to elucidate the polygenic etiology of PD. Based on quantitative global proteomics focused on methyl-arginine modifications, they report upregulation and downregulation of this specific posttranslational modification in several proteins, including some related to mitochondrial biogenesis such as CRTC1 and PSF. Moreover, posttranslational alterations of other identified factors could be required in molecular events linked to PD or other neurodegenerative disorders.
第三个研究文章，“改变线粒体呼吸和帕金森氏病患者Parkin的突变体成纤维细胞线粒体功能的其他功能”，由W. Haylett等，调查线粒体健康帕金-mutant fibroblasts from PD patients. Their results show that mitochondrial respiration and cell growth are higher in these cells, suggesting a compensatory mechanism in the absence of Parkin. Identification of this response could be a therapeutic target to preserve mitochondrial function in PD patients with Parkin mutations.
这期特刊的第四个研究论文，“内源性PGC-1的前馈回路α和Estrogen Related Receptorα调节神经元的电子传递链，”地址关键线粒体监管机构的作用PGC-1αin the activation of the nuclear-encoded mitochondrial electron transport chain (ETC) genes. R. Bakshi et al. show that PGC-1αregulatesERRα转录。有趣的是，他们报告的内源性的是吡格列酮治疗的增加的表达PGC-1α,ERRα, and their ETC target genes. The modulation of the PGC-1α通过药物给药转录网络可能潜在地为PD和其它神经变性疾病临床目标。
在最后审查，“LRRK2及其在帕金森病的细胞功能的活化机理”的作者讨论LRRK2的细胞作用和最近的研究联系起来LRRK2介导的PD线粒体功能障碍和异常的自噬。在这方面，PD相关的突变LRRK2导致受损的激酶和降低的GTP酶活性。因此，激酶抑制剂，以及LRRK2的底物和调节器的表征的发展，是在理解LRRK2发病必不可少和识别用于治疗的潜在目标。
The main purpose of this special issue is to shed light on the relevance of mitochondria as an essential organelle in postmitotic cells such as neurons and how mitochondrial damage contributes to the PD pathogenesis. An accurate and comprehensive understanding of mitochondrial quality control processes is critical to prevent cell death and development of age-related neurodegenerative disorders like PD. Current therapeutic strategies in PD are based on slowing down disease progression; however, they are not successful. New therapeutic approaches should be based on early biomarkers of PD and mitochondrial dysfunction is one promising target to be investigated.
Rubén Gómez-Sánchez
何塞M.布拉沃 - 圣佩德罗
马修E. Gegg
Rosa A. González-Polo
José M. Fuentes
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版权所有©2016鲁本·戈麦斯 - 桑切斯等人。这是下发布的开放式访问文章Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
