Oakland University
Thursday, March 28, 2013

Undergraduates Massoll and Mando publish in Investigative Ophthalmology and Visual Science

Two undergraduate biology majors, Charlotte Massoll and Wasym Mando, are the lead authors on an article “Excitotoxicity Up-Regulates SARM1 Protein Expression and Promotes Wallerianlike Degeneration of Retinal Ganglion Cells and their Axons,” to be published in the journal Investigative Ophthalmology and Visual Science. Their research was carried out with CBR member Shravan Chintala of the Eye Research Institute. Both students participated in the ERI’s Summer Undergraduate Program in Eye Research (SUPER), Massoll in 2011 and Mando in 2012. Excerpts from the introduction of the paper are given below (citations removed).

"Damage to retinal ganglion cells (RGCs) and their axons are major clinical concerns in a number of blinding diseases of the retina, including glaucoma, which affects around 60 million people worldwide. Despite the fact that the elevated intraocular pressure (IOP) has been identified as a risk factor for the degeneration of RGCs in glaucoma, the mechanisms underlying IOP-mediated retinal damage are still unclear. A number of hypotheses have been proposed including alterations in transport of neurotropic factors, retinal ischemia, increase in endothelial nitric oxide synthase (eNOS), reactive gliosis, excitotoxicity, and axonal self-destruction. Among these hypotheses, evidence regarding the role of glutamate in RGC death has been controversial, and, to date, the role of increased levels of glutamate in RGC death in glaucomatous damage has never been substantiated. However, after inducing excitotoxicity by N-methyl-Daspartic acid (NMDA) or kainic acid (KA), a number of studies on rodents and primates have shown that excitotoxicity does play a role in the death of RGCs because antagonists against NMDA and non-NMDA receptors have been shown to offer neuroprotection.

Although studies in animal models of excitotoxicity have shown that NMDA, and non-NMDA receptor antagonists offer neuroprotection, the underlying mechanisms are still not well understood. Previous studies have shown that excitotoxicity causes damage not only to the cell bodies of RGCs, but also to their axons in the retina and optic nerve. When excitotoxicity induces apoptotic death of RGCs, their axons can undergo morphological changes that lead to their fragmentation through an axonal self-destruction process known as Wallerian-degeneration, named after Augustus Waller. This process was traditionally viewed as a passive process due to blockade of neurotropic factors, but a few studies on a mutant mouse strain, Wallerian degeneration slow (WldS), have shown that this degeneration process might be driven by active molecular program similar to apoptotic cell death program. Since WldS is not made under normal conditions, the endogenous mechanisms that promote axonal-self destruction are not well understood. Towards this goal, by employing forward genetic screen in Wallerian-degeneration model of Drosophila melanogaster, a recent study reported that two genes, Drosophila sterile alpha Armadillo motif (dsarm) and its mouse homolog, sterile alpha/Armadillo/Toll-Interleukin receptor homology domain 1 (Sarm1), plays a direct role in axonal-self destruction….

… In this study, we have investigated whether kainic acid-mediated excitotoxicity up-regulates SARM1 protein in the retina, and whether up-regulation of SARM1 protein promotes Wallerian-like degeneration of RGCs and their axons in a transgenic mouse line, B6.Cg-Tg(Thy1-YFPH)2Jrs/J, in which a subset of RGCs and their axons express a yellow fluorescent protein. After inducing excitotoxicity, we have performed fundus imaging on live animals and microscopic analysis of optic nerves before and after KA- or PBS treatment."

The research was supported by a grant from the National Eye Institute (EY017853), and Oakland University Research Excellence Funds.
Two undergraduate biology majors, Charlotte Massoll and Wasym Mando, are the lead authors on an article to be published in the journal Investigative Ophthalmology and Visual Science.

Created by Brad Roth (roth@oakland.edu) on Thursday, March 28, 2013
Modified by Brad Roth (roth@oakland.edu) on Thursday, March 28, 2013
Article Start Date: Thursday, March 28, 2013