New Retinitis Pigmentosa Research: Uncovering the Mechanism Underlying Photoreceptor Cell Death

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Researchers from the National Eye Institute and New York University have published new research that implicates the normally beneficial and protective "trash-collecting" central nervous system cells in the accelerated cell death associated with retinitis pigmentosa.

Please note that this research is in its earliest stages and has been conducted thus far only with laboratory mice. However, a new clinical trial related to this study, Oral Minocycline in Treating Bilateral Cystoid Macular Edema Associated with Retinitis Pigmentosa, is now underway and is recruiting human subjects.

The research, entitled Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration (explained below) has been published in the July 2, 2015 Early Edition of EMBO Molecular Medicine. Molecular Medicine is a peer-reviewed, online open-access journal dedicated to forging new links between clinicians and molecular biologists. Interest areas covered by the journal include aging, angiogenesis, genetics, gene therapy, stem cells, and regenerative medicine.

The authors are Lian Zhao, Matthew K. Zabel, Xu Wang, Wenxin Ma, Parth Shah, Robert N. Fariss, Haohua Qian, Christopher N. Parkhurst, Wen-Biao Gan, and Wai T. Wong, who represent the following institutions: National Eye Institute, National Institutes of Health; and New York University School of Medicine.

Some Terminology to Begin

Here is a brief explanation of the key scientific terms used by the researchers:

  • Microglia: Cells in the central nervous system that function as "scavengers" to attack, ingest, and destroy foreign substances and protect the central nervous system against infection. They act as phagocytes of waste products of the central nervous system.
  • Phagocytes: A type of cell within the body that engulfs, ingests, and destroys foreign particles, bacteria, and cell debris.
  • Phagocytosis: The process by which the cell (phagocyte) engulfs, ingests, and destroys foreign particles. Phagocytosis is a normal process in healthy nervous system tissues and is a key way to clear away dead cells and cellular debris.

About Retinitis Pigmentosa

Retinitis pigmentosa (RP) is part of a large group of hereditary retinal conditions or dystrophies, involving one or several layers of the retina. RP occurs in approximately 1 in 4,000 people in the United States. At present, there is no cure.

A scene as it might be viewed by a person with retinitis pigmentosa

Most persons with RP initially experience difficulty with night vision and in low light levels. Central (straight ahead) vision is usually retained until late in the course of the disease, while peripheral (or side) vision becomes progressively more constricted, resulting in "tunnel vision" (pictured above).

Primarily, the retinal rod cells – light-sensitive, specialized retinal receptor cells that activate at low light levels and provide night vision – are involved, but there may also be some involvement of the retinal cone cells, which function best in relatively bright light and provide color vision and greater visual acuity than do rod cells.

You can read more about retinitis pigmentosa research at What Is Retinitis Pigmentosa? by Frank J. Weinstock, MD, FACS at the VisionAware website.

About the Research

Excerpted from In blinding eye disease, trash-collecting cells go awry, accelerate damage, via Medical Xpress:

Spider-like cells inside the brain, spinal cord, and eye hunt for invaders, capturing and then devouring them. These cells, called microglia, often play a beneficial role by helping to clear trash and protect the central nervous system against infection. But a new study shows that they also accelerate damage wrought by blinding eye disorders, such as retinitis pigmentosa.

Retinitis pigmentosa damages the retina, the light-sensitive tissue at the back of the eye. Research has shown links between retinitis pigmentosa and several mutations in genes for photoreceptors, the cells in the retina that convert light into electrical signals that are sent to the brain via the optic nerve. In the early stages of the disease, rod photoreceptors, which enable us to see in low light, are lost, causing night blindness. As the disease progresses, cone photoreceptors, which are needed for sharp vision and seeing colors, can also die off, eventually leading to complete blindness.

[The research team] studied mice with a mutation in a gene that can also cause retinitis pigmentosa in people. The researchers observed in these mice that very early in the disease process, the microglia [i.e., the trash-devouring cells] infiltrate a layer of the retina near the photoreceptors where they don't usually venture. The microglia then create a cup-like structure over a single photoreceptor, surrounding it to ingest it in a process called phagocytosis.

Phagocytosis is a normal process in healthy tissues and is a key way of clearing away dead cells and cellular debris. However, in retinitis pigmentosa, the researchers found that the microglia target damaged living photoreceptors, in addition to dead ones.

To confirm that microglia contribute to the degeneration process, the researchers genetically eliminated the microglia, which slowed the rate of rod photoreceptor death and the loss of visual function in the mice. The microglia seem to ignore cone photoreceptors, which fits with the known early course of retinitis pigmentosa.

What triggers microglia to go on this destructive feeding frenzy? [Lead researcher] Wong and colleagues found evidence that photoreceptors carrying mutations undergo physiological stress. The stress then triggers them to secrete chemicals dubbed "find me" signals, which is like ringing a dinner bell that attracts microglia into the retinal layer.

Once there, the microglia probe the photoreceptors repeatedly, exposing themselves to "eat me" signals, which then trigger phagocytosis. In response to all the feasting, the microglia become activated. That is, they send out their own signals to call other microglia to the scene and they release substances that promote inflammation.

More about the Research from Molecular Medicine

From the article synopsis, with the full open-access article available online:

  • In retinitis pigmentosa (RP), retinal microglia are shown to potentiate the rate of rod photoreceptor death via phagocytic and pro-inflammatory mechanisms. This process may be common to multiple genetic etiologies of RP in mouse models and in human patients.
  • Microglial phagocytosis of rod photoreceptors was initiated at the start of rod apoptosis [i.e., cell death] with early infiltration of retinal microglia into the outer retina, upregulation of phagocytic molecules in microglia, and exposure of PS, an "eat-me" signal, on rod photoreceptors.
  • Microglial phagocytosis of rods included apoptotic cells [i.e., cells that have died] but also cells that have not yet been committed to apoptosis and are negative for apoptotic markers, indicating microglial clearance of stressed but living rods.
  • Infiltrating microglia demonstrated dynamic interactions with photoreceptors via motile processes that culminate in the overt phagocytosis of non-apoptotic rods.
  • The contribution of infiltrating microglia to rod demise was demonstrated by structural and functional rescue of photoreceptor degeneration.
  • Microglia-directed interventions may be of potential utility in prolonging the survival of photoreceptors and deferring irreversible vision loss associated with RP of different genetic etiologies.

VisionAware will continue to report on this research as results become available. You can watch a video of microglia "eating" rod photoreceptors at YouTube.

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