Membrane-Related Diseases - Membrane Biophysics, Biological and Medical Physics, Biomedical Engineering - page 149

would be incapable of repairing itself, thus destroying it and bringing about
DMD.
The concept of a true or inherent membrane disorder, however, differs from other
disease classes because many diseases involve the membrane to some degree but
are not necessarily centrally affected by membrane abnormalities. Due to the sig-
nificance of membranes in selectively shielding cells from the environment and
interacting with it, it is not surprising that the disruption of membrane function leads
to pathological changes. As discussed at length in this monograph, membranes play
key roles in regulating transport into and out of cells, conferring selective recep-
tivity via protein receptors, anchoring cytoskeletal filaments and structures forming
the extracellular matrix, providing binding sites for enzymatic catalysis, and allow-
ing cell motility. It is, therefore, easy to see why membrane defects lead to cellular
pathologies. In fact, most, diseases involve the membrane as a major factor in disease
etiology. Unfortunately, the existence of diverse multiple effects causing membrane
disruption means that there is no coherent classification scheme of diseases affected
by changes in cell membranes. Determining membrane-based pathologies, identify-
ing the mechanisms that underlie them, and understanding how drugs used to treat
them work is consequently complicated by distinct disruption types. For example,
membrane transport can be affected by changes occurring in membrane proteins, in
the lipid bilayer or in the cytoskeleton. There are also numerous diseases and dis-
orders caused by alterations in the structure of proteins that reside in the membrane
and function as receptors, transporters, enzymes or structural components. Drugs
that target these defects in membrane-protein-based diseases typically interact with
proteins, not membranes, and block, augment or mimic the actions of the protein
involved.
Nonetheless, two categories of true membrane-based diseases can be singled out.
The first are caused by defects in cytoskeletal components that impair membrane
function, while the second occur when altered membrane lipid composition disrupts
trans-membrane transport. The cytoskeleton contains structural proteins linked to
the membrane that provide protection from the stresses generated by many cellular
processes, for example, muscle contraction. Cytoskeletal structures also include sig-
naling complexes close to cell adhesion molecules. Disruptions in the cytoskeleton
can, therefore, lead to a range of diseases, such as sickle-cell anemia and DMD.
Sickle-cell anemia is a genetic disease that results in the production of a defective
form of hemoglobin, which distorts red blood cells into the characteristic sickle shape.
Red blood cells maintain their shape using a network of the cytoskeletal proteins actin
and spectrin. In sickle-cell anemia, the actin/spectrin network malfunctions, making
red blood cells too rigid and causing obstructions in microcirculation [ 11 ]. The main
drug used in the therapy for sickle-cell anemia, hydroxyurea, reduces the forma-
tion of sickle hemoglobin while also decreasing neutrophil numbers which promote
adhesion of sickled cells to blood vessel walls. However, it has also been reported
that hydroxyurea acts directly on the cell membrane. This drug is known to decrease
expression of adhesion molecules on red blood cells including phosphatidylserine
(PS), which is unusually expressed on the outer surface of red blood cells in sickle-cell