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Samuel D Crish, Josephine K Lepp, Matthew Alan Smith, Christine Dengler-Crish, Gina Nicole Wilson; Cytoskeletal changes in the visual projection of the DBA/2J mouse. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2452.
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© ARVO (1962-2015); The Authors (2016-present)
Cytoskeletal changes and deficits in axonal transport are among the earliest hallmarks of many neurodegenerative diseases. Addressing these pre- and early degenerative changes may provide the best opportunity for treating these disorders.<br /> The most commonly affected cytoskeletal proteins in neurodegeneration are neurofilaments, tau, and spectrin as well as related enzymes calpain and p35/p25. Finally, while not a cytoskeletal protein, accumulation of Aβ not only creates structural blockades that hinder transport but also activate kinases that drive pathological phosphorylation. We examined levels and distribution of these proteins in the retinal ganglion cell (RGC) projection in the DBA/2J mouse model of glaucoma.
We traced DBA/2J and DBA/2J-Gpnmb+ mouse retinofugal projections with cholera toxin subunit B (CTB). Superior colliculi (SC) were microdissected based on transport outcome. We quantified pNF-H, Aβ(1-42), total tau, two phosphoisoforms of tau, spectrin breakdown products, calpain-2, and p35/25 in retina, proximal/distal optic nerve (ON), and superior colliculus using ELISA or immunoblotting in pre-glaucomatous, early, and late glaucomatous DBA/2J mice. SC was microdissected based on presence/absence of CTB; corresponding retinal projections were also analyzed based on transport outcome.
Significant elevations in Aβ were observed early in the retina with elevations occurring later in the projection. There were also significant age-dependent and tissue-specific increases in pNF-H in the retina, ON and SC of DBA/2J mice. While retinal pNF-H concentrations were not elevated until the early glaucomatous stage, a significant increase in pNF-H was observed in the SC and ON at the pre-glaucomatous stage, which persisted throughout all ages. Furthermore, elevated pNF-H in SC and corresponding projections with compromised transport was observed. Surprisingly, no clear relationship between total or phosphorylated tau levels and age or transport outcome was detected. We found elevated SBDP, calpain, and both p35/25 in glaucomatous animals.
Overall, these results indicate early cytoskeletal changes in the distal portion of the retinal ganglion cell projection early in glaucoma. Non-cytoskeletal changes appeared early in the retina and may drive the other pathologies. Understanding the progression of these structural alterations in glaucoma may present new therapeutic avenues for this disease
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