Zeineddine Rafaa, Pundavela Jay F, Corcoran Lisa, Stewart Elise M, Do-Ha Dzung, Bax Monique, Guillemin Gilles, Vine Kara L, Hatters Danny M, Ecroyd Heath, Dobson Christopher M, Turner Bradley J, Ooi Lezanne, Wilson Mark R, Cashman Neil R, Yerbury Justin J
Illawarra Health and Medical Research Institute, Wollongong, Australia, 2522.
School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia, 2522.
Mol Neurodegener. 2015 Oct 31;10:57. doi: 10.1186/s13024-015-0053-4.
Amyotrophic Lateral Sclerosis is characterized by a focal onset of symptoms followed by a progressive spread of pathology that has been likened to transmission of infectious prions. Cell-to-cell transmission of SOD1 protein aggregates is dependent on fluid-phase endocytosis pathways, although the precise molecular mechanisms remain to be elucidated.
We demonstrate in this paper that SOD1 aggregates interact with the cell surface triggering activation of Rac1 and subsequent membrane ruffling permitting aggregate uptake via stimulated macropinocytosis. In addition, other protein aggregates, including those associated with neurodegenerative diseases (TDP-43, Httex146Q, α-synuclein) also trigger membrane ruffling to gain entry into the cell. Aggregates are able to rupture unstructured macropinosomes to enter the cytosol allowing propagation of aggregation to proceed.
Thus, we conclude that in addition to basic proteostasis mechanisms, pathways involved in the activation of macropinocytosis are key determinants in the spread of pathology in these misfolding diseases.
肌萎缩侧索硬化症的特征是症状局部发作，随后病理逐渐扩散，这一过程被比作传染性朊病毒的传播。超氧化物歧化酶1（SOD1）蛋白聚集体的细胞间传播依赖于液相内吞途径，尽管确切的分子机制仍有待阐明。
我们在本文中证明，SOD1聚集体与细胞表面相互作用，触发Rac1激活以及随后的膜 ruffling，从而通过刺激的巨胞饮作用实现聚集体摄取。此外，其他蛋白质聚集体，包括与神经退行性疾病相关的聚集体（TDP - 43、Httex146Q、α - 突触核蛋白）也会触发膜 ruffling 以进入细胞。聚集体能够使无结构的巨胞饮小体破裂以进入细胞质，从而使聚集的传播得以进行。
因此，我们得出结论，除了基本的蛋白质稳态机制外，参与巨胞饮作用激活的途径是这些错误折叠疾病中病理扩散的关键决定因素。
