|
Malfunctions in Vision Reactions May Be
the Key to Macular Degeneration
by Philip Filner, Ph. D. Possible Causes of Macular Degeneration The causes(s) of macular degeneration, and the process(es) by which it develops are not yet fully understood. Some have proposed that Age
Related Macular Degeneration is brought on by poor circulation in the blood vessels of the retina, particularly the macula. Others have suggested that it is caused by a decline in the
body's antioxidant systems with age, which serve to destroy harmful free radicals produced in normal metabolism. Deterioration of the antioxidant systems are thought to be a key part
of the aging process. Still others have suggested that macular degeneration is a consequence of environmental insults to the body, which affect some sensitivie people by causing
macular degeneration. While one or more of these suggestions may eventually be shown to be correct for ARMD, recent research progress on hereditary forms of MD, particularly
Stargardt's disease, have led to the development of a fairly coherent and increasingly detailed picture of the disease process. That picture is sketched below. Because there is now
firm genetic evidence that some mutations in the same gene which is believed to cause Stargardt's disease, the abcr gene, also are associated with some cases of ARMD, the description
below is likely to have applicability to at least some ARMD as well. Vision Reactions Light reaching the retina enters the light-sensing structures called rods and cones. Cross Section of Retina (Lens Toward Top) |
|
|
Both rods and cones contain stacks of flat membranes called photoreceptor
outer segment discs, in which are embedded the light-reactive substance called rhodopsin. Rhodopsin consists of a protein called opsin, and a light-absorbing pigment molecule called
cis-retinol, which is made from vitamn A. When cis-retinol absorbs a photon of light, it changes to trans-retinal, which is reduced to trans-retinol and released, and an electrical
impulse destined for the brain is generated. The trans-retinol can be recycled to cis-retinal, but the recycling does not occur in the rods or cones. Trans-retinol is transported
out of the rod or cone to the nearby layer of cells lining the back of the retina, called the Retinal Pigment Epithelium. In those cells the trans-retinol is converted to cis-retinol,
then oxidized back to cis-retinal, which is then returned to the rods and cones, and re-complexed with opsin in the outer segments. The reconstituted complex can then again be used in
the light-sensing reaction. Rim protein, abcr gene and retinal diseases About a year ago, it was discovered that the protein
responsible for transporting trans-retinol out of the outer segments of rods is encoded by the abcr gene. The protein was named Rim protein, because it occurs at the rim of
photoreceptor outer segment discs, before the gene encoding it was characterized and named abcr. Certain mutations in the abcr gene have been found at substantially greater than
chance frequency in people with Stargardt's disease, cone dystrophy, a type of retinitis pigmentosa, and age related macular degeneration. It is therefore almost certain that
mutations in the abcr gene are responsible for a number of different genetic disorders of the retina.
Probable Origins of Lipofuscin and Drusen In transport, trans-retinol and other cis-retinal precursors
are coupled to lipides and specific transport proteins. Those materials have a characteristic green fluorescence which makes it possible to observe deposits of them. Those fluorescent
deposits are located on the cells of the Retinal Pigment Epithelium. The deposits are called lipofuscin. They are a normal part of the biochemical processes in vision. However, in
people with macular degeneration, excessive amounts may accumulate. In addition to recycling of trans-retinol, the rods and cones shed entire "spent" outer segment discs,
which contain lipides and proteins. It is thought that these protein and lipide components also may be recycled, but that in macular degeneration the recycling process malfunctions,
so waste byproducts accumulate. The accumulated waste byproducts are thought to be the origin of yellowish fatty deposits seen on the macula, which are called drusen. Drusen deposits
are typically found between the retinal pigment epithelium and Bruch's membrane. Bruch's membrane separates the cells of the retina from the small blood vessels behind the retina,
in a tissue called the choroid. These blood vessels normally bring nourishment to the cells of the retina, and remove waste products of their metabolism. Possible origin of wet ARMD Sometimes Bruch's membrane gets
damaged. Recently, it has been shown that ruptures of Bruch's membrane permit a protein known as VEGF-1 which occurs in the retinal pigment epithelium to reach the blood vessels,
where it stimulates neovascularization - formation of new blood vessels. Leaky neovascularizations occur in a number of retinal diseases, including wet ARMD. It may be that the basic
difference between dry and wet ARMD is whether or not Bruch's membrane has been ruptured. July 30, 1999 |
|
