Introduction

This book mainly concerns two conditions, both of which show the unusual combination of a progressive neurological disorder and a haemolytic anaemia in which the red cells have a spiky appearance, known as acanthocytosis. The first condition is known as 'chorea-acanthocytosis' (ChAc) [30]. This is an autosomal recessive disorder, while the condition known as 'McLeod' is X-linked. ChAc is caused by changes in the VPS13A (formerly CHAC) gene [48], one of the so-called ' VPS13' family, while McLeod syndrome [15] is caused by changes in the gene XK [31]. Although the mutant genes have both been cloned, the diseases remain difficult to treat, at least in part because the underlying pathological mechanisms are poorly understood. The fact that two completely different proteins can cause virtually identical diseases suggests that the protein products of these two genes are components of the same pathway.

The combination of red cell and neurological pathology is an unusual one, although not unknown [24]. Presumably there is some common molecular mechanism that is shared between red cell and basal ganglia neurons. The point of this chapter is to look at the disease from the point of view of the red cell (and in particular its abnormal shape), to see what knowledge about the neuropathology might be gleaned from considerations of the simpler haematological cell.

We will look at the red cells from the point of view of what can be called 'membrane bending'. As is well known, biological membranes consist of a lipid bilayer, composed of phospholipids in two sheets, their hydrophobic acyl chains facing each other. To the phospholipids is added a considerable proportion of cholesterol, which is thought to lie alongside the acyl chains. The whole is studded with proteins that penetrate the bilayer, and in turn is underpinned and supported by an interconnecting protein scaffold or cytoskeleton that confers order and structure on the lipid bilayer, which forms a flexible seal. As will be seen below, the cytoskeleton forms a geodesic filamentous meshwork on the cytoplasmic surface of the membrane.

The lipids are present in fixed proportions (Fig. 1). The mechanism that controls these proportions in the face of free (if slow) exchange with the plasma is unclear [67]. The lipids have a sidedness, in that essentially all of the phosphatidylserine (PS) and phosphatidylinositol (PI) are internally facing (Fig. 1). Sphingomyelin (SM) and phosphatidylcholine (PC) are largely in the outer leaflet. This asymmetry is maintained at least partly by a kind of pump known as a flipase (also spelt 'flip-pase'), whose molecular identity remains elusive [18]. In the red cell and probably all other human cells, the lipids are laterally organised into domains relatively enriched or depleted in cholesterol and sphingomyelin.

The plasma membrane of a neurone is basically similar, but is of course much more complex. Like the red cell it must be flexible and durable, but it has a huge signalling job, receiving, transmitting and relaying action potential signals. It must

Fig. 1 Relative proportions of lipids in the inner and outer leaflets of the human red cell membrane. The different bars represent the different lipids (SM, sphingomyelin; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; PI, phosphatidylinositol and phosphorylated derivatives, PA, phosphatidic acid; GL, glycolipids). The vertical position denotes the relative distribution of the lipid between inner and outer leaflets. The width of the bar denotes the relative molar proportion of each lipid. There is a very substantial amount of cholesterol (nearly half of all lipid). The phospholipids with negatively charged headgroups (PS, PI) are entirely confined to the inner leaflet, while the glycolipids are all external. SM, PC and PE can be found in either leaflet, although PC and SM are predominantly in the outer and PE in the inner

Fig. 1 Relative proportions of lipids in the inner and outer leaflets of the human red cell membrane. The different bars represent the different lipids (SM, sphingomyelin; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; PI, phosphatidylinositol and phosphorylated derivatives, PA, phosphatidic acid; GL, glycolipids). The vertical position denotes the relative distribution of the lipid between inner and outer leaflets. The width of the bar denotes the relative molar proportion of each lipid. There is a very substantial amount of cholesterol (nearly half of all lipid). The phospholipids with negatively charged headgroups (PS, PI) are entirely confined to the inner leaflet, while the glycolipids are all external. SM, PC and PE can be found in either leaflet, although PC and SM are predominantly in the outer and PE in the inner make correct connections with many other neurones. The neuronal membrane has electrical activity related to its many ion channels; it has receptors to receive information; and a synaptic system to release packets of chemicals to tell other neurones what to do. One feature that is common to both red cells and neurones is their comparatively long life in relation to their housekeeping machinery. Neurones must last the life of the organism and cannot, in general, be replaced, although they have a nucleus with apparatus for protein and lipid synthesis to allow internal renewal. The red cell has no nucleus but nevertheless must survive a punishing 3-month existence without access to new protein synthesis.

The idea of 'membrane bending' was originated by Sheetz and Singer [61], working on the red cell. Devoid of intracellular organelles and equipped with a simple two dimensional cytoskeleton which simply underpins the lipid bilayer, the easily accessible red cell can be deformed by simple forces acting within the membrane. Sheetz and Singer doctored the composition of the lipid sheet by choosing compounds that intercalated selectively into either the outer leaflet or the inner. If the outer layer was expanded the cell developed externally facing protrusions to become either an acanthocyte or an echinocyte; if the inner leaflet was enlarged, the cell took on an invaginated shape known as a stomatocyte (Fig. 2). The theoretical basis of this idea was later extended [64].

Sheetz and Singer interpreted these data in terms of the 'bilayer couple'. In mechanics, a 'couple' is a pair of forces acting in opposite, anti-parallel directions which typically serve to rotate an object about an axis. In the membrane context, the anti-parallel forces act in the planes of the membrane, expanding or contracting one leaflet compared to the other. Instead of the rotation that would occur in mechanics, the 'bilayer couple' deforms, or folds, or bends, the membrane.

For some years these ideas remained confined to the red cell community. More recently the processes behind membrane bending have been closely investigated by cell biologists in more complex cell types, recently reviewed [34, 40, 70]. In cell biology, the main interest in membrane bending centres on the processes of budding, vesiculation and subsequent fusion involved in the trafficking between the different membrane components of the intracellular compartment, mainly endoplasmic reticulum and Golgi. Studies of these organelles have revealed many insights into different aspects of membrane bending. The principles are generic; they are applicable to all biological membranes.

Modern ideas on membrane bending have recently been reviewed [40]. In broad terms, bending can occur by three main mechanisms; (a) manipulation of lipid, (b) bending by the concerted action of the cytoskeleton, and (c) by individual integral or directly membrane-associated proteins, whose conformations endow curvature on a lipid membrane. The ideas and systems in these modern appreciations of membrane bending will be compared with the latest and most comprehensive study of the proteomics of the red cell, which describes a total of nearly 600 proteins in the cytosol

Stomatocytes (inwardly bent) Acanthocytes (outwardly bent)

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