Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases

Abstract

Alzheimer, Parkinson and other neurodegenerative diseases involve a series of brain proteins, referred to as ‘amyloidogenic proteins’, with exceptional conformational plasticity and a high propensity for self-aggregation. Although the mechanisms by which amyloidogenic proteins kill neural cells are not fully understood, a common feature is the concentration of unstructured amyloidogenic monomers on bidimensional membrane lattices. Membrane-bound monomers undergo a series of lipid-dependent conformational changes, leading to the formation of oligomers of varying toxicity rich in β-sheet structures (annular pores, amyloid fibrils) or in α-helix structures (transmembrane channels). Condensed membrane nano- or microdomains formed by sphingolipids and cholesterol are privileged sites for the binding and oligomerisation of amyloidogenic proteins. By controlling the balance between unstructured monomers and α or β conformers (the chaperone effect), sphingolipids can either inhibit or stimulate the oligomerisation of amyloidogenic proteins. Cholesterol has a dual role: regulation of protein–sphingolipid interactions through a fine tuning of sphingolipid conformation (indirect effect), and facilitation of pore (or channel) formation through direct binding to amyloidogenic proteins. Deciphering this complex network of molecular interactions in the context of age- and disease-related evolution of brain lipid expression will help understanding of how amyloidogenic proteins induce neural toxicity and will stimulate the development of innovative therapies for neurodegenerative diseases.

Apolipoprotein A-I Associated Amyloidoses: The Intriguing Case of a Natively Unfolded Protein Fragment

“…Mechanistic studies with well defined model membranes have shown that natively unfolded polypeptides, upon interaction with surfaces, readily adopt helical structures that represent key intermediates in amyloid formation process (Abedini & Raleigh, 2009). In particular, anionic surfaces and anionic phospholipid-rich membranes can play key roles either in triggering protein fibrillogenesis by acting as conformational catalysts for amyloid fibrils deposition (Fantini & Yahi, 2010), or as inhibitors of fibrillogenesis (Zhu & Fink, 2003). We demonstrated that the conformation of the fibrillogenic polypeptide [1-93]ApoA-I is largely affected by membrane-mimicking structures, such as liposomes (Monti et al, 2010).…”

“…The general concept that biological surfaces may influence and direct molecular assemblies is gaining increasing attention. It is known that the interaction of natively folded proteins with groups exposed on a membrane surface often modifies their conformational states (Fantini & Yahi, 2010;Shanmugam & Jayakumar, 2004;Kakio et al, 2004). On the other hand, unfolded polypeptide chains can gain ordered structures at the membrane surface or inside the bilayer (Fantini & Yahi, 2010).…”

“…It is known that the interaction of natively folded proteins with groups exposed on a membrane surface often modifies their conformational states (Fantini & Yahi, 2010;Shanmugam & Jayakumar, 2004;Kakio et al, 2004). On the other hand, unfolded polypeptide chains can gain ordered structures at the membrane surface or inside the bilayer (Fantini & Yahi, 2010). Conversely, proteins can alter membrane fluidity, and/or permeate the membrane bilayer and can even extract lipids from it (Hou et al, 2005).…”

Computer-Aided Design of Novel HIV-1 Entry Inhibitors Based on Glycosphingolipids

“…Эти результаты согласуются с экспериментальными данными (см., например, обзор [35]), свидетельствующими о том, что важным фактором, обеспечивающим энергетическую стабилизацию комплексов β-GalCer с белками, являются XH···π водородные связи остатка сахара с ароматическими аминокислотами. В частности, исследования -амилоидного и PrP пептидов, использующих β-GalCer для проникновения в клетку-мишень, показали [36,37], что ключевую роль в связывании играют XH···π взаимодействия углеводной части гликолипида с остатками их ароматических аминокислот.…”

“…3), определяет специфичность их связывания с белком gp120 ВИЧ-1. Правомерность этого предположения подтверждает тот факт, что остаток жирной кислоты молекулы β-GalCer, с помощью которой вирус внедряется в некоторые чувствительные клетки, отличные от макрофагов и Т-лимфоцитов [9,10], погружен вглубь мембраны, а наиболее доступным элементом структуры гликолипида является пиранозное кольцо галактозы [35]. О важном вкладе остатка галактозы -GalCer в Примечания: а Аминокислотные остатки петли V3, образующие π-стэкинг с ароматическими фрагментами боковых цепей гликолипидов группы I; б Аминокислотные остатки петли V3, участвующие в XH···π взаимодействиях с пиранозным кольцом галактозы гликолипидов; в Межмолекулярные водородные связи.…”