Mitochondrial dysfunction and neurodegenerative proteinopathies: mechanisms and prospects for therapeutic intervention.
Mitochondrial dysfunction and neurodegenerative proteinopathies: mechanisms and prospects for therapeutic intervention.
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DOI：
10.1042/bst20180025
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发表时间：
2018-08-20
影响因子：
3.9
通讯作者：
Hicks AR
中科院分区：
文献类型：
--
作者：
Briston T;Hicks AR
神经退行性蛋白质病是一组病理学相似的神经系统进行性疾病，其特征在于易感蛋白质的结构改变和毒性错误折叠。Aβ、tau、α-突触核蛋白和TDP-43的寡聚化导致毒素功能获得或丧失，从而导致在阿尔茨海默病、帕金森病、肌萎缩性侧索硬化和额颞叶痴呆中观察到的表型。错误折叠的蛋白质会对线粒体产生不利影响，有丝分裂后的神经元对代谢功能障碍特别敏感。错误折叠的蛋白质损害线粒体动力学（形态学和运输），阻止功能性线粒体到达突触，ATP利用的主要位点。此外，错误折叠的蛋白质与线粒体的直接关联可能沉淀或增加功能失调的氧化磷酸化和线粒体质量控制，导致在疾病中观察到的氧化还原稳态异常。因此，一个显着的兴趣在于理解神经退行性疾病中的线粒体毒性机制，并在解剖这些机制，以维持疾病中的线粒体稳态。最近在理解神经控制的细胞死亡途径和阐明线粒体渗透性孔生物结构方面的进展开始为靶向神经变性提供新的途径。去泛素化酶的新型线粒体作用正在显现，并为一类新的蛋白质提供了一个机会，以促进线粒体自噬和泛素-蛋白酶体系统为目标进行治疗。大脑的新陈代谢非常活跃，非常重视维持ATP的供应。因此，确定维持线粒体功能的机制可能是所有蛋白质病的共同干预点。
Neurodegenerative proteinopathies are a group of pathologically similar, progressive disorders of the nervous system, characterised by structural alterations within and toxic misfolding of susceptible proteins. Oligomerisation of Aβ, tau, α-synuclein and TDP-43 leads to a toxin gain- or loss-of-function contributing to the phenotype observed in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. Misfolded proteins can adversely affect mitochondria, and post-mitotic neurones are especially sensitive to metabolic dysfunction. Misfolded proteins impair mitochondrial dynamics (morphology and trafficking), preventing functional mitochondria reaching the synapse, the primary site of ATP utilisation. Furthermore, a direct association of misfolded proteins with mitochondria may precipitate or augment dysfunctional oxidative phosphorylation and mitochondrial quality control, causing redox dyshomeostasis observed in disease. As such, a significant interest lies in understanding mechanisms of mitochondrial toxicity in neurodegenerative disorders and in dissecting these mechanisms with a view of maintaining mitochondrial homeostasis in disease. Recent advances in understanding mitochondrially controlled cell death pathways and elucidating the mitochondrial permeability pore bioarchitecture are beginning to present new avenues to target neurodegeneration. Novel mitochondrial roles of deubiquitinating enzymes are coming to light and present an opportunity for a new class of proteins to target therapeutically with the aim of promoting mitophagy and the ubiquitin–proteasome system. The brain is enormously metabolically active, placing a large emphasis on maintaining ATP supply. Therefore, identifying mechanisms to sustain mitochondrial function may represent a common intervention point across all proteinopathies.