Sorting out release, uptake and processing of alpha-synuclein during prion-like spread of pathology.
Sorting out release, uptake and processing of alpha-synuclein during prion-like spread of pathology.
复制标题
DOI：
10.1111/jnc.13449
复制
发表时间：
2016-10
影响因子：
4.7
通讯作者：
Brundin P
中科院分区：
文献类型：
--
作者：
Tyson T;Steiner JA;Brundin P
帕金森病是一种进行性神经系统疾病，其特征在于形成主要由蛋白质α-突触核蛋白的错误折叠和聚集形式组成的细胞内蛋白包涵体。越来越多的证据支持α-突触核蛋白进展的朊病毒样假说。该假说假定α-突触核蛋白是朊病毒样病理因子，并负责脑中帕金森病理学的进展。由于环境或遗传（或更可能是两者的组合）的某种损伤，可能在周围神经系统中发生的α-突触核蛋白的潜在错误折叠或聚集，可能扩散到中脑，最终导致黑质神经元变性。随着疾病的进一步发展，α-突触核蛋白病理学可能继续扩散到整个大脑，包括皮质，导致认知和更高的大脑功能恶化。虽然α-突触核蛋白最初错误折叠和聚集的原因尚不清楚，但关于细胞如何处理异常的α-突触核蛋白组装已经了解了很多。在这篇综述中，我们专注于这些机制，并讨论他们在试图定义的作用，他们可能发挥的传播错误折叠的α-突触核蛋白从细胞到细胞。α-突触核蛋白病理学的朊病毒样假说提出了一种错误折叠的α-突触核蛋白从一个神经元传递到另一个神经元的方法。该假说假定错误折叠的α-突触核蛋白变得易于聚集，并且当释放并被邻近细胞吸收时，引发进一步的错误折叠和聚集。在这篇综述中，我们研究了参与α-突触核蛋白加工的细胞机制，以及这些机制如何有助于α-syn的朊病毒样传播。
Parkinson’s disease is a progressive neurological disorder that is characterized by the formation of intracellular protein inclusion bodies composed primarily of a misfolded and aggregated form of the protein α-synuclein. There is growing evidence that supports the prion-like hypothesis of α-synuclein progression. This hypothesis postulates that α-synuclein is a prion-like pathological agent and is responsible for the progression of Parkinson pathology in the brain. Potential misfolding or aggregation of α-synuclein that might occur in the peripheral nervous system as a result of some insult, environmental or genetic (or more likely a combination of both) that might spread into the midbrain, eventually causing degeneration of the neurons in the substantia nigra. As the diseases progresses further it is likely that α-synuclein pathology continues to spread throughout the brain, including the cortex, leading to deterioration of cognition and higher brain functions. While it is unknown why α-synuclein initially misfolds and aggregates, a great deal has been learnt about how the cell handles aberrant α-synuclein assemblies. In this review we focus on these mechanisms and discuss them in an attempt to define the role that they might play in the propagation of misfolded α-synuclein from cell-to-cell. The prion-like hypothesis of α-synuclein pathology suggests a method for the transmission of misfolded α-synuclein from one neuron to another. This hypothesis postulates that misfolded α-synuclein becomes aggregation prone and when released and taken up by neighboring cells, seeds further misfolding and aggregation. In this review we examine the cellular mechanisms that are involved in the processing of α-synuclein and how these may contribute to the prion-like propagation of α-syn.