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Gina Nicole Wilson, Denise M Inman, Samuel D Crish; Cytoskeletal and mitochondrial-related protein changes within the DBA/2J retinal projection. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2533.
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© ARVO (1962-2015); The Authors (2016-present)
Early mitochondrial dynamics dysregulation, cytoskeletal derangement, and axonal transport deficits are involved in glaucomatous neurodegeneration. However, the time course and relationship between these pathologies is poorly understood. We examined levels of mitochondrial proteins, the cytoskeletal protein tau, and related kinases in the DBA/2J mouse model of glaucoma.
Retina, optic nerve (ON), and superior colliculi (SC) were collected from mixed-sex DBA/2J and DBA/2J-Gpnmb+ mice at pre-glaucomatous (3-5 mo), early glaucomatous (8-10 mo) and late glaucomatous (12-15 mo) ages (n=22 mice, 44 projections). Cholera toxin subunit B (CTB) was used to trace the retinal projections; SC were microdissected and analyzed based on transport outcome. Bead-based multiplex analyses or ELISAs were used to quantify PARK5, PARK7, α-synuclein, tau, ptau-231, and activated ERK1/2 (pERK1/2). Co-immunoprecipitation was used to identify a possible mechanism of tau translocation to the RGC soma.
Retinal PARK5 and PARK7 levels were twice as high in late glaucomatous mice compared to controls. However, PARK 5 was highest in pre-glaucomatous SC and ON, decreasing from approximately 3ng/µg to 1ng/µg by 12-15 mo. PARK7, however, peaked in ON and SC of 8-10 mo DBA/2Js. α-synuclein was 3-fold higher in pre-glaucomatous SC (~100 pg/mg compared to 300 pg/mg), while retinal levels remained consistent across ages.Tau becomes phosphorylated early within the SC and later translocates to RGCs by 12-15 months of age. An open question in neurodegeneration concerns the mechanism of tau translocation. Co-IP shows hyperphosphorylation of tau by GSK3β increases binding affinity to the retrograde motor assembly.Levels of retinal pERK1/2 were significantly elevated 2-3 fold in 8-10 mo DBA/2Js compared to controls and young DBA/2Js. Between 8-10 and 12-15 mo, retinal pERK fell by 45%. A similar relationship appeared in the ON.
We propose that increased tau phosphorylation occurs first within the distal part of the RGC projection, followed by specific elevations in mitochondrial PARK7. PARK7 levels in ON parallel pERK levels; suggesting that PARK7-mediated ERK activation further drives tau phosphorylation and pathological progression. As these changes precede transport loss, they may provide beneficial therapeutic targets focused on restoring functional changes in glaucoma.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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