The research was conducted at LSU Health Sciences Center New Orleans and the papers are entitled Neurotrophins enhance retinal pigment epithelial cell survival through neuroprotectin D1 signaling and Photoreceptor outer segment phagocytosis attenuates oxidative stress-induced apoptosis with concomitant neuroprotectin D1 synthesis. RPE cells are responsible for the renewal of the tips of photoreceptor cells (rods and cones) crucial to vision.

Neuroprotectin D1 is a messenger (mediator) discovered by Nicolas Bazan, MD, PhD, Boyd Professor, Ernest C. and Yvette C. Villere Professor of Ophthalmology, and Director of the Neuroscience Center of Excellence at LSU Health Sciences Center New Orleans, and his colleagues that represents one of the most powerful endogenous (made by the body) neuroprotective mediators known. Its precursor is DHA (docosahexaenoic acid), an essential fatty acid (must be provided by the diet) of the omega-3 fatty acid family enriched in RPE cells in the retina and brain. DHA is a target of oxidative stress in pathological conditions and Dr. Bazan's research recently showed that RPE cells create NPD1 in response to oxidative stress.

The LSUHSC scientists discovered that neurotrophins (small proteins critical in cell survival and death) trigger NPD1 synthesis. They demonstrate that the endogenous toxic component (A2E) that accumulates in the retina during aging and in retinal degenerations, including those due to gene mutations, can be counteracted by NPD1.

The LSUHSC research team conducted studies on the formation and action of NPD1 on a human transformed cell line called ARPE-19. They also used primary human RPE cells and found that they also synthesize NPD1. The researchers showed that neurotrophins regulate NPD1 by stimulating its production and also controlling its release. They found that the neurotrophin PEDF not only sparks the production of NPD1, but it acts synergistically with DHA indicating that the availability of the NPD1 initial precursor is critical for its synthesis.

To answer the question about whether or not NPD1 could prevent cell death caused by an excess of A2E known to accumulate in the RPE during aging and to be exaggerated in age-related macular degeneration, the researchers added NPD1 to an A2E-induced experimental model and found it not only stopped programmed cell death, but that the protective effects were present even six hours later. The team decided to explore whether oxidative stress triggered by another experimental condition, called serum starvation/H2O2/TNF, would be similarly inhibited. NPD1 also exerted protection in this experimental condition. Addition of NPD1 even eight hours after triggering oxidative stress resulted in protection. In a series of further experiments to delineate how NPD1 acts, the scientists found that NPD1 elicits a specific action rather than antioxidant activity to counteract A2E-induced cell death in RPE cells.

One of these papers reports also the discovery that the daily interaction of photoreceptors and RPE cells balance against damage is maintained by NPD1.

"The regulation of these proteins involved in cell survival or death shown by this research will help us define NPD1 survival bioactivity in the RPE cell," notes Dr. Bazan. "These events are clinically significant because they may allow the exploration of therapeutic interventions for retinal degenerative diseases such retinitis pigmentosa."

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But the real breakthroughs came through collaboration. Hauser said that individually, none of the six centers in the consortium could have completed a study of this scale and complexity, but by using a Collaborative Research Award from the National MS Society, they were able to form a truly effective international consortium that could deliver the most exhaustive search for MS risk factors ever published.

The consortium paper is among a series of recent whole-genome association studies that have begun to uncover the genetic basis of complex diseases like diabetes, schizophrenia, and coronary artery disease. Unlike diseases caused by a mutation in a single gene, these conditions seem to arise from a combination of genetic, behavioral and environmental factors.

Jorge Oksenberg, PhD, a UCSF neurology professor who has been involved in the development of the UCSF collection for more than a decade, said that it wasn't until scientists were able to combine the potential of both repositories with the intellectual and financial resources of previously competing research teams that they were able to make the connections represented in these studies.

"For studying these complex genetic diseases, where we're looking at many genes contributing and each one contributing just a little bit, we need a very large group of patients and controls," said Oksenberg, who, along with Hauser, worked on both the consortium research and the study for the "Nature Genetics" paper. "We're looking for genetic markers that we know are common in the population at large, but they're somehow more common in the MS patients, and when combined, they make the patient more susceptible to getting MS."

Genomic technologies have now made it possible to uncover these subtle genetic associations. The next step is to begin to collect larger numbers of samples and examine more DNA sequences, which will allow scientists to identify subtler variations that contribute to the disease.

"Despite all the hype and new technology, the genome is still mysterious to us," Oksenberg said. "This has opened a new window into MS genetics. Now we need to understand what these chains are doing."

The international collaboration is currently planning even larger and more detailed explorations of the genetic landscape of MS and is now committed to making the entire data set available to MS researchers worldwide.

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