Lipid rafts, protein scaffolds, and neurologic disease

Abstract

Lipid rafts are specialized microdomains of the plasma membrane that interact with proteins involved in vesicular transport and signaling mechanisms. Lipid rafts are enriched in cholesterol, sphingolipids, and scaffolding proteins, such as caveolins and septins.1–5 Although the precise functions of lipid rafts are still controversial and largely based on in vitro studies there is evidence that lipid rafts and associated scaffolding proteins may be involved in the pathogenesis of neurologic disease. For example, mutations of caveolin-3 have been associated with phenotypically diverse muscle disorders.6 Lipid rafts may also be the site of abnormal processing of amyloid precursor protein and prion protein.7 Impaired septin 4 function may contribute to synuclein accumulation and neurotoxicity in Parkinson disease (PD).8–10 There are several comprehensive reviews on the composition and potential functions of lipid rafts and their associated scaffold proteins.1–5,10 This brief review selectively focuses on some of these concepts that may have implications for neurologic disease. The plasma membrane is a lipid bilayer organized into discrete compartments or microdomains through lipid-lipid, lipid-protein, and membrane-cytoskeletal interactions.1,2 Lipids rafts are microdomains that are particularly rich in cholesterol and sphingolipids (glycolipids and sphingomyelin) and act as platforms for colocalization and interaction of proteins involved in vesicular transport, signaling mechanisms, and other functions2–4 (table). Proteins associated with lipid rafts include cell surface proteins that are attached to the membrane by a glycosyl phosphatidylinositol (GPI) anchor and proteins are that covalently modified by conjugation with saturated fatty acids, such as palmitic acid, present in the sphingolipids side chain. Lipid rafts are also characterized by their interactions with the cytoskeleton.1,2 Two types of lipid rafts are caveolae (little caves, figure) and planar lipid rafts.4 View this table: Table Some of the proteins associated with lipid rafts and potential functional implications Figure Examples of possible …