Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases.
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 beta-sheet structures (annular pores, amyloid fibrils) or in alpha-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 alpha or beta 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.
Fantini
Jacques
J
Laboratoire des Interactions Moléculaires et Systèmes Membranaires, Marseille, France. jacques.fantini@univ-cezanne.fr
Yahi
Nouara
N
D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism*
D000682:Amyloid; D013107:Sphingolipids; D002784:Cholesterol
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