Department of Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea; Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea.
Department of Life Science, Kyonggi University, Suwon, South Korea.
Biochem Biophys Res Commun. 2021 Jan 1;534:561-567. doi: 10.1016/j.bbrc.2020.11.042. Epub 2020 Nov 22.
Huntington's disease (HD) is caused by a mutant huntingtin (mHtt) protein that contains abnormally extended polyglutamine (polyQ) repeats. The process of autophagy has been implicated in clearing mHtt aggregates, and microRNAs (miRNAs) have been reported as new players to regulate autophagy. However, the autophagy-associated target molecule of let7b miRNA remains unclear in HD. The present study showed that extended polyQ in mouse striatal neurons increased lysosomal membrane-associated protein 2A (LAMP2A) levels and influenced the inflammatory conditions, and these augmented levels correlated to the let7b miRNA expression level. The upregulated let7b increased LAMP2A and reduced the extended polyQ in mouse striatal cells. The let7b level was highly expressed in the striatum of pre-onset HD mice, whereas it was significantly reduced in the post-onset HD striatum. Considering the level changing pattern of let7b, LAMP2A protein levels were increased in the striatum of pre-onset HD mice, but decreased in the striatum of post-onset HD mice. These results suggest that LAMP2A related to chaperone-mediated autophagy (CMA) capacity might play an important role in HD symptom onset and progression.
亨廷顿病（HD）是由含有异常延长的多聚谷氨酰胺（polyQ）重复的突变亨廷顿蛋白（mHtt）引起的。自噬过程已被牵涉到清除 mHtt 聚集体中，并且已经报道了 microRNAs（miRNAs）作为新的调节自噬的因子。然而，在 HD 中，let7b miRNA 的自噬相关靶分子仍然不清楚。本研究表明，小鼠纹状体神经元中的延长多聚 Q 增加了溶酶体膜相关蛋白 2A（LAMP2A）的水平并影响了炎症状态，并且这些增加的水平与 let7b miRNA 的表达水平相关。上调的 let7b 增加了 LAMP2A 并减少了小鼠纹状体细胞中的延长多聚 Q。let7b 的水平在发病前 HD 小鼠的纹状体中高度表达，而在发病后 HD 纹状体中则显著降低。考虑到 let7b 的水平变化模式，LAMP2A 蛋白水平在发病前 HD 小鼠的纹状体中增加，但在发病后 HD 纹状体中降低。这些结果表明，与伴侣介导的自噬（CMA）能力相关的 LAMP2A 可能在 HD 症状的发作和进展中发挥重要作用。
