BACKGROUND 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. RESULTS 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. CONCLUSION 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.

中文翻译：

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SOD1蛋白聚集体刺激神经元中的巨胞饮作用，以促进其传播。

背景技术肌萎缩性侧索硬化症的特征在于症状的局部发作，随后是病理学的逐步蔓延，其类似于感染性病毒的传播。尽管精确的分子机制仍有待阐明，但SOD1蛋白聚集体的细胞间传播取决于液相内吞途径。结果我们在本文中证明SOD1聚集体与细胞表面相互作用，从而触发Rac1的激活，随后的膜起皱允许通过刺激的巨胞饮作用吸收聚集体。另外，其他蛋白质聚集体，包括与神经退行性疾病相关的那些聚集体（TDP-43，Httex146Q，α-突触核蛋白）也触发膜起皱以进入细胞。聚集体能够使未结构化的大体胶体破裂，进入胞质溶胶，从而使聚集体的繁殖得以继续进行。结论因此，我们得出的结论是，除了基本的蛋白稳态机制外，参与巨胞饮作用的途径是这些错叠疾病中病理学传播的关键决定因素。