Amyloid proteins raft lipids

Ehehalt, R., KeUer, P., Haass, C., Thiele, C., Simons, K. (2003) Amyloidogenic processing of the Alzheimer P-amyloid precursor protein depends on lipid rafts. J. Cell. Biol., 160, 113-123. 

Pizzo, P. and Viola, A. 2004. Lipid rafts in lymphocyte activation. Microbes Infect 6, 686-692. Rallidis, L.S., Paschos, G., Liakos, G.K., Velissaridou, A.H., Anastasiadis, G., and Zampelas, A. 2003. Dietary alpha-linolenic acid decreases C-reactive protein, serum amyloid A and interleukin-6 in dyslipidaemic patients. Atherosclerosis 167, 237-242. 

FIGURE 6.12 Interaction of a disordered amyloid protein with a lipid raft domain. In the upper panel, the... 

Lipid rafts play both global and specific roles that contribute to control the conformation of amyloid proteins. The first effect is a reduction of dimensionality, a process that occurs for each soluble molecule transferred from the bulk extracellular water phase (a 3D space) to a... 

FIGURE 8.5 Structuration of an IDP upon binding to membrane lipids. When an IDP comes close to a membrane, specific interactions with selected lipids (such as gangliosides in lipid rafts) will favor the efficient adhesion of the protein to this membrane. Moreover, the repetitive head groups of raft lipids wiU induce a-helical folding of the protein through a typical chaperone-facilitated reaction. The reduction of dimensionality from 3D (extracellular milieu) to 2D (hpid raft surface) also favors the concentration of the protein on the membrane surface. The Parkinson s and Alzheimer s disease-associated proteins a-synuclein and p-amyloid peptides (Ap) are typical examples of such IDPs that acquire a helical structure when bound to hpid rafts of neural cells. 

However, when the proteins fall on tiie 2D surface of the membrane, tiiis distance is significantly decreased. The effect is potentiated by tiie fact that the attachment of the amyloid protein on the membrane is not stochastic. Indeed, a common feature of amyloid proteins is that they have a marked preference for glycosphingolipids (e.g., gangliosides) that are concentrated in relatively small microdomains of tiie plasma membrane (lipid rafts). Thus, landing on a lipid raft will result in an important concentration of the amyloid protein, and this effect is potentiated by the reduction of dimensionality (Fig. 8.5). Moreover, the head groups of glycolipid clusters will exert a chaperone effect that forces the amyloid protein to adopt a secondary structure, which, depending on the protein-lipid stoichiome, can be either an a-helix or a (3-rich stmcture. ... 

FIGURE 8.6 Pore formation by amyloid proteins a membrane-assisted process. Amyloid proteins that have acquired an a-helical structure upon binding to Kpid rafts can penetrate the membrane. The presence of cholesterol rmderneath the glycosphingoHpids (GSL) in lipid raft areas stimulates both the insertion of the protein within the membrane and its oligomerization into Ca -permeable pores. 

This survey of the intrinsic and environmental factors that govern the oligomerization and aggregation properties of amyloid proteins indicates that lipid rafts exert an important control on these phenomena. Individual cases of lipid-amyloid interactions are discussed in the following chapters. However, at this stage, we should mention that raft lipids... 

Deciphering tiie molecular mechanisms by which lipid rafts interact with amyloid proteins and control their oligomerization/aggregation into neurotoxic superstructures is a prerequisite for developing these new therapeutic strategies. The discovery of strikingly common mechanisms shared by distinct amyloid proteins raises some hope for the discovery of a common cure for all these diseases. 

Parkin ET, Turner AJ, Hooper NM. Amyloid precursor protein, although partially detergent-insoluble in mouse cerebral cortex, behaves as an at)fpical lipid raft protein. Biochem J. 1999 344(Pt l) 23-30. 

The two partners are the membrane and the infectious protein (e.g., Alzheimer s -amyloid peptide Ap, Parkinson s associated a-synuclein, and HIV-1 gpl20) (Fig. 14.1A-C). Each of these proteins faces a complex membrane formed by a collection of lipids with wide biochemical diversity. Hopefully, among the myriad of brain membrane lipids, the protein generally selects a preferred target, most often located in a lipid raft microdomain. For instance, Ap peptides interact preferentially with ganglioside GMl, and a-synuclein with GM3. ... 

We propose to use the chimeric a-s5m34M5/HH peptide as a competitive inhibitor of the binding of amyloid proteins to lipid raft microdomains of brain cells. As schematized... 

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