A Novel Role for the Lysosome in Macular Degeneration

With age, harmful waste products accumulate in cells as a normal side-effect of cellular processes. Some of these cannot be easily degraded and build up inside the recycling units called lysosomes, especially in the long-lived cells of the nervous system. This includes retinal cells, and there this process contributes to conditions such as macular degeneration. Lysosomes become bloated and dsyfunctional, unable to perform their normal tasks of braking down waste and damaged cellular structures. Here, researchers identify another essential role for lysosomes in retinal cells, and it is not unreasonable to propose that this, too, suffers because of the build up of waste materials. The SENS approach to this problem is to create new drugs, usually based on mining the bacterial world for suitable enzymes, that can break down some of the worst of the problem waste compounds. This is presently under active development at Ichor Therapeutics.

A research team has pinpointed how immune abnormalities beneath the retina result in macular degeneration, a common condition that often causes blindness. Although macular degeneration eventually damages or kills the light-sensitive rods and cones, it starts with injury to the retinal pigment epithelium (RPE). The RPE, a single layer of cells beneath the rods and cones at the back of the eye, performs many functions essential for healthy vision. The damage starts with a disturbance of immune proteins called complement, which normally kill disease-causing organisms by boring holes in their cell membranes.

"The light-detecting cells in the retina are totally dependent on the RPE for survival. but the RPE cells are not replaced through the lifespan. So we asked, 'What are the innate protective mechanisms that keep the RPE healthy, and how do they go awry in macular degeneration?'" Researchers focused on two protective mechanisms: the protein CD59, which regulates complement activity when attached to the outside of RPE cells; and lysosomes, spherical structures that plug pores created by the complement attack. Together, they offer an in-depth defense. "CD59 prevents the final step of attack that forms the pore. Once a pore forms, the cell can move a lysosome to close it."

If the complement attack is not defeated, the opening in the RPE cell membrane allows the entry of calcium ions, which spark a long-term, low-grade inflammation that inhibits both protective mechanisms, creating a vicious cycle of destruction. The inflammation in the RPE damages mitochondria, structures that process energy inside all cells. This could eventually lead to a decline or death of the photoreceptor cells, once they are deprived of their essential housekeepers. The result is the loss of central, high-resolution vision. Crucially, the study identified the enzyme aSMase that is activated by excess cholesterol in the RPE, which neutralizes both protective mechanisms, and found that drugs such as desipramine used to treat depression neutralized that enzyme and restored the protection - and the health of RPE cells - in a mouse model.

Link: http://news.wisc.edu/macular-degeneration-insight-identifies-promising-drugs-to-prevent-vision-loss/

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