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Vivek Kumar Gupta, Nitin Chitranshi, Kanishka Pushpitha, Mehdi Mirzaei, Stuart L Graham; Novel Modulation of Endogenous Tau protein by Shp2 tyrosine Phosphatase in the Retina. Invest. Ophthalmol. Vis. Sci. 2019;60(9):635.
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© ARVO (1962-2015); The Authors (2016-present)
Tau is a multi-functional microtubule-associated protein with a critical role in neurodegenerative disorders including Alzheimer's disease (AD). It is increasingly recognized that glaucoma shares several pathological features with AD and retinal tau protein has been shown to be affected in acutely elevated intraocular pressure (IOP) model. Our recent studies demonstrated that upregulation of Shp2 which is a non-receptor tyrosine phosphatase, promotes retinal ganglion cell (RGC) injury. Genetic knockdown of Shp2 in glaucoma, conversely exhibits neuroprotective effects on the RGCs. Here, we investigated retinal Tau expression and phosphorylation profile in a chronic glaucoma model and evaluated the effects of Shp2 modulation on this microtubule associated protein.
Anterior chamber microbead injections (Sprague-Dawley rats, weekly, 2 months) were performed to induce chronically elevated IOP (20.84±1.65 mm Hg). Shp2 expression changes in the glaucomatous retinas were investigated using WB and IF. Further, Shp2 and Shp2-shRNA constructs were designed under the regulatory control of CAG hybrid promoter linked with GFP in AAV2. These constructs were administered intravitreally to either over-express or knockdown Shp2 specifically in the RGCs (2 months, n=40). Modulatory effects of Shp2 on Tau expression and phosphorylation were studied using IF and WB followed by densitometric quantification.
Exposure to chronically elevated IOP resulted in significantly enhanced Tau (Ser404) protein phosphorylation in the glaucoma retinas as observed using immunoblot analysis (p<0.05). IF analysis of glaucomatous retinal sections further exhibited Tau hyperphosphorylation in the inner retinal layers. AAV mediated Shp2 upregulation revealed increased Tau phosphorylation in the RGCs in retinal sections. Increased pTau (Ser404) (p<0.024, ANOVA, Tukey’s test) was also evident in the WB of Shp2 over-expressing retinas compared to GFP controls.
This study identifies novel regulatory effects of Shp2 on endogenous Tau (Ser404) protein phosphorylation in the retina. We further demonstrate that chronically elevated IOP leads to increased phosphorylation of Tau (Ser404) protein. These findings imply that modulation of Shp2 could have applications to understand glaucoma and potentially other neurodegenerative disorders involving Tau pathology.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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