New Research Reveals Unexpected Biological Pathway In Glaucoma
Caption: Low-power scanning EM view of the optic nerve head shows that astrocyte somata are also transversely oriented at the onset of myelination. In both the lamina (shown here) and the postlaminar ONH myelination transition zone (MTZ) granule accumulations exist as swellings and protrusions in axons (Left), as large evulsions completely separated from axons and completely ensheathed by astrocytes (Center), and as accumulations within the cytoplasm of astrocytes (Right). (Scale bars: 1 μm.)
Study is first to pinpoint the precise anatomical location where vision loss appears to occur in glaucoma
In a study published in the Proceedings of the National Academy of Sciences, a team of researchers from the Kennedy Krieger Institute and four collaborating institutions, identified a new and unexpected biological pathway that appears to contribute to the development of glaucoma and its resulting vision loss.
Prior research has suggested that the optic nerve head, the point where the cables that carry information from the eye to the brain first exit the eye, plays a role in glaucoma. In this study, researchers report a series of findings that offer novel insights into cellular and molecular mechanisms operating at the optic nerve head in two mouse models of glaucoma. Most notably, they discovered that at a specific location within the optic nerve head, there is a unique populations of cells called astrocytes that demonstrate properties that appear to make them a critical factor in the visual blinding that occurs in glaucoma. The eureka moment in this work came when the team of researchers visualized the cellular structures responsible for a previously unrecognized transfer of material from normal retinal ganglion cells axons of the optic nerve head to astrocytes, where degradation of what were once axonal proteins appears to be carried out. The realization that this previously uncharacterized material transfer system existed occurred when a new 3D imaging method being developed at the National Center for Microscopy and Imaging Research (NCMIR) at UC San Diego was applied in this collaborative project with Johns Hopkins researchers.
Further, in this same location, researchers found abnormal forms of a protein called gamma synuclein that is similar to abnormal forms of alpha synuclein, a related protein known for its key role in cell loss in Parkinson's disease. The findings suggest that a biological process similar to Parkinson’s disease unfolds in glaucoma at the specific anatomical location pinpointed in this study for the first time.
Finally, using new NCMIR imaging technologies, researchers discovered that at this anatomical location, there is a surprising process whereby astrocytes remove the debris of neurons, the cells that die in neurodegenerative disorders such as glaucoma. It is likely that this newly discovered process involving removal of the debris of one cell by a neighboring cell is important not only in glaucoma and Parkinson’s disease, but also for many neurodegenerative diseases.
"These findings are very exciting because they give us several novel targets for future interventions," said Dr. Nicholas Marsh-Armstrong, senior study author and a research scientist at Kennedy Krieger Institute. "I believe these findings put us on the cusp of discovering a treatment for glaucoma that may also have relevance for a number of other neurodegenerative diseases."
Future studies will examine this novel pathway and molecular/cellular mechanism to understand precisely what steps go awry in glaucoma and what can be controlled pharmacologically to identify interventions that slow the disease progression.
Some of the data for this study, including the following data sets, are available at the Cell Centered Database (CCDB): MP 8391 (http://ccdb.ucsd.edu/sand/main?mpid=8391&event=displaySum) and MP 8398 (http://ccdb.ucsd.edu/sand/main?mpid=8093&event=displaySum)
Dr. Marsh-Armstrong and other scientists at Kennedy Krieger Institute collaborated on this study with colleagues at the Johns Hopkins University School of Medicine, University of California at San Diego, Cardiff University in England, and the University of Murcia in Spain.
This research was principally supported by the Melza M. and Frank Theodore Barr Foundation through the Glaucoma Research Foundation, with additional grant funding provided in part by the International Retinal Research Foundation and the National Eye Institute of the National Institutes of Health.
Glaucoma is a neurodegenerative disorder that causes blindness by damaging the optic nerve, which sends signals from the eye to the brain. It affects more than 60 million people and is the second leading cause of blindness worldwide. While older individuals are at higher risk for the disease, babies and children are also susceptible to glaucoma, especially those with certain neurological disorders.
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(Adapted from materials provided by Kennedy Krieger Institute—http://www.kennedykrieger.org/ kki_news.jsp?pid=9329
Judy V. Nguyen, Ileana Soto, Keun-Young Kim, Eric A. Bushong, Ericka Oglesby, Francisco J. Valiente-Soriano, Zhiyong Yang, Chung-Ha O. Davis, Joseph L. Bedont, Janice L. Son, John O. Wei, Vladimir L. Buchman, Donald J. Zack, Manuel Vidal-Sanz, Mark H. Ellisman, and Nicholas Marsh-Armstrong. Myelination transition zone astrocytes are constitutively phagocytic and have synuclein dependent reactivity in glaucoma. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.1013965108