Remarkable difference of phospholipid molecular chirality in regulating PrP aggregation and cell responses  

作　　者：Cunli Wang Xue Wang Dongdong Wang Shengxu Qian Fusheng Zhang Mingyang Li Minmin Li Wenqi Lu Bo Liu Guangyan Qing 

机构地区：[1]School of Biomedical Engineering,Dalian University of Technology,Dalian 116024,China [2]CAS Key Laboratory of Separation Science for Analytical Chemistry,Dalian Institute of Chemical Physics,Chinese Academy of Sciences,Dalian 116023,China [3]College of Chemistry and Chemical Engineering,Wuhan Textile University,Wuhan 430200,China

出　　处：《Chinese Chemical Letters》2023年第2期236-243,共8页中国化学快报（英文版）

基　　金：supported by the National Natural Science Foundation of China (Nos. 21775116 and 21922411);DICP Innovation Funding (Nos. DICP-RC201801 and DICP I202008);Liao Ning Revitalization Talents Program (No. XLYC1802109)。

摘　　要：Prion diseases are fatal neurodegenerative diseases that can cause severe dementia.The misfolding and accumulation of the prion peptide (PrP)_(106–126) is crucial,and this process is closely relevant to biological membranes.However,how PrP_(106–126)aggregation is affected by the molecular chirality of phospholipid membrane is unknown.Thus,in this study,a pair of L-and D-aspartic acid (Asp)-modified 1,2-dipalmitoyl-sn–glycero-3-phosphoethanolamine (DPPE) were synthesized to construct chiral liposomes.We discover that L-Asp-DPPE liposomes strongly inhibit the oligomerization and amyloidogenesis of PrP_(106–126),whether acting on monomers or oligomers,which rescues cytotoxicity induced by PrP_(106–126).By comparison,D-Asp-DPPE liposomes inhibit peptide oligomerization only at a high concentration and cannot prevent amyloidogenesis when acting on oligomers,which lead to pronounced cytotoxicity.Apoptosis experiment,dynamic change of intracellular Ca^(2+)(_(i)Ca^(2+)) and Ca^(2+)release from endoplasmic reticulum(ER),reactive oxygen species (ROS) production,adsorption dynamics and affinity tests,and fluorescent imaging clearly disclose that molecular chirality of the liposomes dominates conformational transition of PrP_(106–126)from random coil to β-sheet,binding and adsorption of the monomers and oligomers,and subsequent fibrillation process,resulting in distinct inhibition effect in Ca^(2+)overload and release,ROS production and cell apoptosis.This work is the first to report that interfacial molecular chirality is a potentially crucial influence on the fibrillation process of PrP_(106–126) and its cell responses,whereas the convergence of chiral amino acids and liposomes can be considered potential inhibitors in prion diseases.

关 键 词：Prion disease LIPOSOME CHIRALITY Interface Cytosolic Ca^(2+) 

分 类 号：R914[医药卫生—药物化学]