A connection between blindness and Parkinson’s disease

A research team led by Paulo A. Ferreira at Duke University Medical Center and collaborators at Cleveland Clinic led by Neal Peachey has found a promising genetic link between blindness and Parkinson’s disease. This discovery, the researchers say, opens doors for new treatments of age-related disorders. The team’s study was published in the Journal of Biological Chemistry.

The researchers set out to understand better the role of Ran-binding protein 2, or Ranbp2, in the retinal pigment epithelium, a tissue that lines the back of the eye. The retinal pigment epithelium, or RPE, is a critical component of the blood–retinal barrier, which helps to maintain the homeostasis of the neuroretina. Aging, toxic environmental insults and genetics lead to age-related macular degeneration and retinitis pigmentosa, and these diseases ultimately lead to blindness. In addition, the RPE produces L-DOPA, an intermediate chemical compound required for dopamine production. Dopamine is crucial for communication of dopaminergic neurons. When these dopaminergic neurons begin to die widely for reasons that are not well understood yet, patients develop Parkinson’s disease.

Ferreira’s interest in neurodegenerative diseases goes back to his graduate and postdoctoral work, when he was searching for proteins with chaperone activity in neurons of the retina. He discovered a large and multimodular protein, Ranbp2, and then set out to gain a better understanding of its partners and find out the biological and physiological functions of the interactions between Ranbp2 and its partners.

3-D-confocal images of RPE of wild-type mice (top) and knock-out Ranbp2 mice with extrusion of degenerating RPE cells (bottom). Ribbon representation of the structure of the binary complex of a Ran-binding domain of Ranbp2 with Ran-GTP (middle).

Ferreira’s new study in the JBC reports that mice with overall functional deficits in Ranbp2 develop degeneration of the RPE and secondary breakdown of the blood&nash;retinal barrier. This loss of Ranbp2 in the RPE has features that resemble those of a severe form of age-related macular degeneration, wet AMD, which is characterized by abnormal blood vessels and bleeding in the back of the eye. Further, the researchers pinpointed a selective biochemical activity of Ranbp2 that, when lost, sufficed to recapitulate the degeneration of the RPE. This Ranbp2 activity is implicated in controlling nucleocytoplasmic trafficking of selective substrates.

Ferreira’s team also found that the mice that lacked overall Ranbp2 activities also developed robust juvenile Parkinsonian tremors. Interestingly, loss of the biochemical activity of Ranbp2 that controls nucleocytoplasmic trafficking and causes RPE degeneration did not promote Parkinson’s in mice. The observation that loss of Ranbp2 causes Parkinsonism in mice did not come as a complete surprise to the Ferreira laboratory, because they knew that mice with reduced levels of Ranbp2 are predisposed to toxicity for the Parkinsonian neurotoxin, MPTP, which is highly damaging to dopaminergic neurons of the midbrain and retina. In addition, other groups had found that Ranbp2 is a substrate for degradation by Parkin, a ubiquitin-ligase whose impairment causes familial and sporadic Parkinson’s disease or multisite oncogenesis.

Based on the results of their study, Ferreira and co-workers concluded that (1) distinct mechanisms and functions of Ranbp2 promote RPE degeneration and Parkinsonism and (2) Parkinsonism is controlled by Ranbp2 and other genetic modifiers, because not all mice lacking Ranbp2 develop Parkinson’s, but mice with Parkinson’s must have loss of Ranbp2 function. Understanding the connections between blindness and Parkinson’s and factors determining the development of these diseases is crucial, because it will help in the development of much-needed therapeutic strategies with multiple clinical applications in neurodegenerative conditions.

“This (study) is a classical example of twists and turns of science and an example of what Louis Pasteur once said: ‘Chance favors only the prepared mind,’” Ferreira said. The study provides “an excellent basis to help us understand the development of novel therapeutic approaches toward multiple diseases.”

Martina Efeyini Martina Efeyin is a toxicologist and freelance writer. Read her blog. She also writes for the National Society of Black Engineers and ScientistaFoundation.com.