Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, 3-39-22, Showa-machi, Maebashi, Gunma, 371-8511, Japan.
Accelerator Laboratory, High Energy Accelerator Research Organization, 1-1 Oho, Tsukuba, Ibaraki, 305-0801, Japan.
Sci Rep. 2021 Dec 6;11(1):23441. doi: 10.1038/s41598-021-02889-6.
In polyalanine (PA) diseases, the disease-causing transcription factors contain an expansion of alanine repeats. While aggregated proteins that are responsible for the pathogenesis of neurodegenerative disorders show cell-to-cell propagation and thereby exert toxic effects on the recipient cells, whether this is also the case with expanded PA has not been studied. It is also not known whether the internalized PA is toxic to recipient cells based on the degree of aggregation. In this study, we therefore prepared different degrees of aggregation of a peptide having 13 alanine repeats without flanking sequences of PA disease-causative proteins (13A). The aggregated 13A was spontaneously taken up by neuron-like cultured cells. Functionally, strong aggregates but not weak aggregates displayed a deficit in neuron-like differentiation in vitro. Moreover, the injection of strong but not weak 13A aggregates into the ventricle of mice during the neonatal stage led to enhanced spontaneous motor activity later in life. Thus, PA in the extracellular space has the potential to enter adjacent cells, and may exert toxicity depending on the degree of aggregation.
在多聚丙氨酸（PA）疾病中，致病转录因子包含丙氨酸重复序列的扩展。虽然负责神经退行性疾病发病机制的聚集蛋白表现出细胞间传播，并因此对受体细胞产生毒性作用，但扩展的 PA 是否也是如此尚未得到研究。也不知道根据聚集程度，内化的 PA 是否对受体细胞有毒。因此，在这项研究中，我们制备了没有 PA 疾病致病蛋白侧翼序列的具有 13 个丙氨酸重复的肽的不同程度的聚集物（13A）。聚集的 13A 被神经元样培养细胞自发摄取。在功能上，强聚集物而不是弱聚集物显示体外神经元样分化缺陷。此外，在新生期将强但不是弱 13A 聚集物注射到小鼠脑室中，会导致其在以后的生活中自发运动活动增强。因此，细胞外空间中的 PA 有可能进入相邻细胞，并可能根据聚集程度产生毒性。
