Mitochondrial function and autophagy: integrating proteotoxic, redox, and metabolic stress in Parkinson's disease.
Mitochondrial function and autophagy: integrating proteotoxic, redox, and metabolic stress in Parkinson's disease.
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DOI：
10.1111/jnc.14308
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发表时间：
2018-03
影响因子：
4.7
通讯作者：
Darley-Usmar V
中科院分区：
文献类型：
--
作者：
Zhang J;Culp ML;Craver JG;Darley-Usmar V
帕金森病（Parkinson's disease，PD）是一种广泛存在于大脑中的神经退行性疾病。在PD死后脑中观察到显著的氧化、还原、代谢和蛋白毒性改变。线粒体功能的改变导致生物能量健康下降是重要的，需要进一步检查，以帮助开发PD严重程度和预后的生物标志物。现在越来越清楚的是，对代谢和信号通路的多次打击可能会加剧PD的发病机制。事实上，从遗传和基因组关联研究中获得的数据已经暗示了控制蛋白质质量控制和代谢的基因的相互作用。例如，已发现负责通过称为线粒体自噬的过程清除功能障碍的线粒体的关键蛋白质的丢失导致PD，并且与PD相关的基因的显著比例编码参与自噬-溶酶体途径的蛋白质。在这篇综述中，我们强调了线粒体的蛋白质毒性，氧化还原和代谢应激和自噬监测在维持线粒体质量的作用的证据。此外，我们总结了α-突触核蛋白，LRRK 2和tau在调节线粒体功能和自噬中的作用。在可以压倒线粒体质量控制机制的应激源中，我们将讨论4-羟基壬烯醛（HNE）和一氧化氮。自噬的影响取决于环境，因此可能具有有益和有害的影响。此外，我们强调了靶向线粒体和自噬功能作为综合治疗策略的潜力，以及微生物组对PD易感性的新贡献。这篇综述提供了关于病理蛋白质，内源性产生的活性物质，环境毒素，代谢，包括葡萄糖和脂肪酸代谢，线粒体自噬功能的多方面影响，在帕金森病的背景下，最近的观察重点。该综述还讨论了未来的研究设计有针对性的策略，以帮助治疗帕金森病。
Parkinson’s disease (PD) is a movement disorder with widespread neurodegeneration in the brain. Significant oxidative, reductive, metabolic, and proteotoxic alterations have been observed in PD postmortem brains. The alterations of mitochondrial function resulting in decreased bioenergetic health is important and needs to be further examined to help develop biomarkers for PD severity and prognosis. It is now becoming clear that multiple hits on metabolic and signaling pathways are likely to exacerbate PD pathogenesis. Indeed, data obtained from genetic and genome association studies have implicated interactive contributions of genes controlling protein quality control and metabolism. For example, loss of key proteins that are responsible for clearance of dysfunctional mitochondria through a process called mitophagy has been found to cause PD, and a significant proportion of genes associated with PD encode proteins involved in the autophagy-lysosomal pathway. In this review, we highlight the evidence for the targeting of mitochondria by proteotoxic, redox and metabolic stress and the role autophagic surveillance in maintenance of mitochondrial quality. Furthermore, we summarize the role of α-synuclein, LRRK2, and tau in modulating mitochondrial function and autophagy. Among the stressors that can overwhelm the mitochondrial quality control mechanisms, we will discuss 4-hydroxynonenal (HNE) and nitric oxide. The impact of autophagy is context depend and as such can have both beneficial and detrimental effects. Furthermore, we highlight the potential of targeting mitochondria and autophagic function as an integrated therapeutic strategy and the emerging contribution of the microbiome to PD susceptibility. This review provides highlights on recent observations regarding the multifacet impact of pathological proteins, endogenously produced reactive species, environmental toxins, and metabolism including glucose and fatty acid metabolism, on mitochondria - autophagy function, in the context of Parkinson’s disease. The review also discuss future studies of designing targeted strategies to aid the treatment of Parkinson’s Disease.
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DOI：
10.1016/s0140-6736(17)31585-4
发表时间：
2017-10-07
期刊：
Lancet (London, England)
影响因子：
--
作者：
Athauda D;Maclagan K;Skene SS;Bajwa-Joseph M;Letchford D;Chowdhury K;Hibbert S;Budnik N;Zampedri L;Dickson J;Li Y;Aviles-Olmos I;Warner TT;Limousin P;Lees AJ;Greig NH;Tebbs S;Foltynie T
通讯作者：
Foltynie T
影响因子：
15.1
作者：
Belluzzi E;Gonnelli A;Cirnaru MD;Marte A;Plotegher N;Russo I;Civiero L;Cogo S;Carrion MP;Franchin C;Arrigoni G;Beltramini M;Bubacco L;Onofri F;Piccoli G;Greggio E
通讯作者：
Greggio E
影响因子：
15.1
作者：
Baranyi M;Porceddu PF;Gölöncsér F;Kulcsár S;Otrokocsi L;Kittel Á;Pinna A;Frau L;Huleatt PB;Khoo ML;Chai CL;Dunkel P;Mátyus P;Morelli M;Sperlágh B
通讯作者：
Sperlágh B
影响因子：
15.1
作者：
Benitez BA;Davis AA;Jin SC;Ibanez L;Ortega-Cubero S;Pastor P;Choi J;Cooper B;Perlmutter JS;Cruchaga C
通讯作者：
Cruchaga C
影响因子：
7.4
作者：
Badia, Mari-Carmen;Giraldo, Esther;Vina, Jose
通讯作者：
Vina, Jose