Islam Md Imamul, Hossain Md Selim, Park Il-Seon
Department of Medical Sciences, Republic of Korea.
Department of Cellular and Molecular Medicine, Chosun University, Gwanju, 501-759, Republic of Korea.
Biochem Biophys Rep. 2020 Oct 26;24:100839. doi: 10.1016/j.bbrep.2020.100839. eCollection 2020 Dec.
Amyloid-β (Aβ), a peptide implicated in Alzheimer's disease, was shown to cause specific fragmentation of lamin proteins, which was mediated by an unidentified protease named nuclear scaffold protease (NSP) independently of caspase-6. Because caspase-6 is responsible for the fragmentation process in many other damage-induced apoptosis, here we further investigated possible involvement of caspase-6 in Aβ-induced lamin fragmentation under various conditions. We found that lamin A fragment generated by NSP (named fragment b) disappeared in cells incubated with Aβ42 for prolonged periods and this product was preserved by a caspase-6 inhibitor. Furthermore, caspase-6 could remove fragment b in nuclei isolated from Aβ42-treated cells (ANU). Lamin B in ANU was fragmented by caspase-6 only after treatment with an alkaline phosphatase. The caspase-mediated fragmentation of lamin B was also achieved with nuclei isolated from cells incubated with Aβ42 plus a Cdk5 inhibitor. The results indicate that Aβ42 induces NSP-mediated fragmentation of lamin A and the following removal process of fragment b by caspase-6 and an Aβ-induced phosphorylation prevents the fragmentation of lamin B by caspase-6. The pathway leading to lamin protein fragmentation in this investigation appears to be specific for Aβ and thus the data will provide novel insights into the toxicity of the peptide.
淀粉样β蛋白（Aβ）是一种与阿尔茨海默病相关的肽，已被证明可导致核纤层蛋白的特异性断裂，这是由一种名为核支架蛋白酶（NSP）的未知蛋白酶介导的，与半胱天冬酶-6无关。由于半胱天冬酶-6在许多其他损伤诱导的细胞凋亡中负责断裂过程，因此我们在此进一步研究了在各种条件下半胱天冬酶-6在Aβ诱导的核纤层蛋白断裂中的可能作用。我们发现，由NSP产生的核纤层蛋白A片段（称为片段b）在与Aβ42长时间孵育的细胞中消失，并且该产物可被半胱天冬酶-6抑制剂保留。此外，半胱天冬酶-6可以去除从Aβ42处理的细胞（ANU）中分离出的细胞核中的片段b。ANU中的核纤层蛋白B仅在用碱性磷酸酶处理后才被半胱天冬酶-6断裂。用从与Aβ42加Cdk5抑制剂孵育的细胞中分离出的细胞核也实现了半胱天冬酶介导的核纤层蛋白B的断裂。结果表明，Aβ42诱导NSP介导的核纤层蛋白A断裂以及随后半胱天冬酶-6去除片段b的过程，并且Aβ诱导的磷酸化可防止半胱天冬酶-6介导的核纤层蛋白B断裂。本研究中导致核纤层蛋白断裂的途径似乎对Aβ具有特异性，因此这些数据将为该肽的毒性提供新的见解。
