The relevance of contact-independent cell-to-cell transfer of TDP-43 and SOD1 in amyotrophic lateral sclerosis.
The relevance of contact-independent cell-to-cell transfer of TDP-43 and SOD1 in amyotrophic lateral sclerosis.
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DOI：
10.1016/j.bbadis.2017.07.007
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Kumita JR
中科院分区：
文献类型：
--
作者：
Hanspal MA;Dobson CM;Yerbury JJ;Kumita JR
肌萎缩侧索硬化症 (ALS) 是一种神经退行性疾病，涉及中枢神经系统 (CNS) 受影响细胞中 TDP-43 和 SOD1 等蛋白质形成细胞质聚集物。病理学从最初的发病部位扩散到邻近的解剖区域。有证据表明，对于疾病相关蛋白，包括 TDP-43 和 SOD1，非天然蛋白构象异构体可以促进天然折叠对应物的错误折叠，并且病理聚集体的细胞间转移可能是疾病在整个中枢神经系统中传播的基础。各种研究表明，SOD1 由神经元样细胞释放到周围的培养基中，无论是游离状态还是封装在细胞外囊泡（如外泌体）中。然后，细胞外 SOD1 可以被在该条件培养基中孵育的幼稚细胞内化，导致内源性细胞内 SOD1 错误折叠和聚集；通过连续通道传播的效果。在与蛋白质错误折叠和进行性神经系统疾病相关的其他蛋白质中也观察到了类似的现象，包括 tau、α-突触核蛋白以及哺乳动物和酵母朊病毒。使用 TDP-43 的条件培养基实验尚不那么有结论，这种蛋白质进行细胞间转移的证据并不那么简单。在这篇综述中，我们描述了 TDP-43 和 SOD1 的特性，并研究了它们各自通过条件培养基参与细胞间转移的能力的证据，并讨论了细胞间转移性质的变化如何表明许多不同的机制参与了 ALS 病理学的传播。运动神经元疾病中蛋白质聚集体在细胞之间转移。细胞接触独立机制可能是一种转移途径。 SOD1 通过细胞培养物中的条件培养基进行细胞间转移。目前尚不清楚 TDP-43 是否持续进行细胞间转移，两种蛋白质之间的差异可能可以解释这一观察结果。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving the formation of cytoplasmic aggregates by proteins including TDP-43 and SOD1, in affected cells in the central nervous system (CNS). Pathology spreads from an initial site of onset to contiguous anatomical regions. There is evidence that for disease-associated proteins, including TDP-43 and SOD1, non-native protein conformers can promote misfolding of the natively folded counterparts, and cell-to-cell transfer of pathological aggregates may underlie the spread of the disease throughout the CNS. A variety of studies have demonstrated that SOD1 is released by neuron-like cells into the surrounding culture medium, either in their free state or encapsulated in extracellular vesicles such as exosomes. Extracellular SOD1 can then be internalised by naïve cells incubated in this conditioned medium, leading to the misfolding and aggregation of endogenous intracellular SOD1; an effect that propagates over serial passages. A similar phenomenon has also been observed with other proteins associated with protein misfolding and progressive neurological disorders, including tau, α-synuclein and both mammalian and yeast prions. Conditioned media experiments using TDP-43 have been less conclusive, with evidence for this protein undergoing intercellular transfer being less straightforward. In this review, we describe the properties of TDP-43 and SOD1 and look at the evidence for their respective abilities to participate in cell-to-cell transfer via conditioned medium, and discuss how variations in the nature of cell-to-cell transfer suggests that a number of different mechanisms are involved in the spreading of pathology in ALS. Protein aggregates transfer between cells in motor neuron disease. Cell contact-independent mechanisms may be a route of transfer. SOD1 undergoes cell-to-cell transfer via conditioned medium in cell culture. It is still unclear whether TDP-43 consistently undergoes cell-to-cell transfer Differences between the two proteins may explain this observation.
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