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

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. This work is the first to report the effect of chiral liposome on the the fibrillation process of PrP 106-126 and its cell responses.