Jiang Peizhou, Gan Ming, Yen Shu-Hui, Moussaud Simon, McLean Pamela J, Dickson Dennis W
Neuropathology Laboratory, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Acta Neuropathol. 2016 Jul;132(1):77-91. doi: 10.1007/s00401-016-1542-4. Epub 2016 Feb 2.
Cell-to-cell transmission of α-synuclein (αS) aggregates has been proposed to be responsible for progressive αS pathology in Parkinson disease (PD) and related disorders, including dementia with Lewy bodies. In support of this concept, a growing body of in vitro and in vivo experimental evidence shows that exogenously introduced αS aggregates can spread into surrounding cells and trigger PD-like pathology. It remains to be determined what factor(s) lead to initiation of αS aggregation that is capable of seeding subsequent propagation. In this study we demonstrate that filamentous αS aggregates form in neurons in response to apoptosis induced by staurosporine or other toxins-6-hydroxy-dopamine and 1-methyl-4-phenylpyridinium (MPP+). Interaction between αS and proaggregant nuclear factor(s) is associated with disruption of nuclear envelope integrity. Knocking down a key nuclear envelop constituent protein, lamin B1, enhances αS aggregation. Moreover, in vitro and in vivo experimental models demonstrate that aggregates released upon cell breakdown can be taken up by surrounding cells. Accordingly, we suggest that at least some αS aggregation might be related to neuronal apoptosis or loss of nuclear membrane integrity, exposing cytosolic α-synuclein to proaggregant nuclear factors. These findings provide new clues to the pathogenesis of PD and related disorders that can lead to novel treatments of these disorders. Specifically, finding ways to limit the effects of apoptosis on αS aggregation, deposition, local uptake and subsequent propagation might significantly impact progression of disease.
α-突触核蛋白（αS）聚集体的细胞间传播被认为是帕金森病（PD）及相关疾病（包括路易体痴呆）中αS进行性病变的原因。支持这一概念的体外和体内实验证据越来越多，表明外源性引入的αS聚集体可扩散到周围细胞并引发类似PD的病变。尚待确定哪些因素导致能够引发后续传播的αS聚集的起始。在本研究中，我们证明丝状αS聚集体在神经元中因星形孢菌素或其他毒素（6-羟基多巴胺和1-甲基-4-苯基吡啶鎓（MPP+））诱导的凋亡而形成。αS与促聚集核因子之间的相互作用与核膜完整性的破坏有关。敲低关键的核膜组成蛋白核纤层蛋白B1可增强αS聚集。此外，体外和体内实验模型表明，细胞破裂时释放的聚集体可被周围细胞摄取。因此，我们认为至少一些αS聚集可能与神经元凋亡或核膜完整性丧失有关，使胞质α-突触核蛋白暴露于促聚集核因子。这些发现为PD及相关疾病的发病机制提供了新线索，可能带来这些疾病的新治疗方法。具体而言，找到限制凋亡对αS聚集、沉积、局部摄取及后续传播影响的方法可能会显著影响疾病进展。
