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ARS Home » Midwest Area » Ames, Iowa » National Animal Disease Center » Virus and Prion Research » Research » Publications at this Location » Publication #359341

Research Project: Pathobiology, Genetics, and Detection of Transmissible Spongiform Encephalopathies

Location: Virus and Prion Research

Title: Retinopathy in a mouse model of Parkinson’s disease: seeding of synucleinopathy induces accumulation of phosphorylated alpha-synuclein (pSer129) and tau, neuroinflammation, metabolic dysregulation, and cell death

item MAMMADOVA, N - Iowa State University
item Kokemuller, Robyn
item SUMMERS, C - Iowa State University
item HE, Q - Iowa State University
item DING, S - Iowa State University
item BARON, T - French Agency For Food, Environmental And Occupational Health & Safety (ANSES)
item YU, C - Iowa State University
item VALENTINE, R - Iowa State University
item SAKAGUCHI, D - Iowa State University
item KANTHASAMY, A - Iowa State University
item Greenlee, Justin
item WEST GREENLEE, M - Iowa State University

Submitted to: Prion
Publication Type: Abstract Only
Publication Acceptance Date: 5/14/2018
Publication Date: 5/22/2018
Citation: Mammadova, N., Kokemuller, R., Summers, C.M., He, Q., Ding, S., Baron, T., Yu, C., Valentine, R.J., Sakaguchi, D.S., Kanthasamy, A.G., Greenlee, J.J., West Greenlee, M.H. 2018. Retinopathy in a mouse model of Parkinson's disease: seeding of synucleinopathy induces accumulation of phosphorylated alpha-synuclein (pSer129) and tau, neuroinflammation, metabolic dysregulation, and cell death. Prion 2018, May 22-25, 2018, Santiago de Compostela, Spain. Paper No. P144. p. 149-150.

Interpretive Summary:

Technical Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by accumulation of misfolded alpha-synuclein within the central nervous system. Visual problems in PD patients are common, although retinal pathology associated with PD is not well understood. The purpose of this study was to investigate retinal pathology in a transgenic mouse model (TgM83) expressing the human A53T alpha-synuclein mutation, and assess the effect of alpha-synuclein "seeding" on the development of retinal pathology. Two-month-old TgM83 mice were intracerebrally inoculated with brain homogenate from old, clinically ill (12-18 months) TgM83 mice. Retinas were then analyzed at 5 months of age. We analyzed retinas from 5-month-old and 8-month-old uninoculated healthy TgM83 mice, and old (12-18 months) mice that were euthanized following the development of clinical signs. Retinas of B6C3H mice (genetic background of the TgM83 mouse) served as control. We used immunohistochemistry and western blot analysis to detect accumulation of alpha-synuclein, pTauThr231, inflammation, changes in macroautophagy, and cell death. Raman spectroscopy was used to test the potential to differentiate between retinal tissues of healthy mice and diseased mice. This work demonstrates retinal changes associated with the A53T mutation. Retinas of non-inoculated TgM83 mice had accumulation of alpha-synuclein, "pre-tangle" tau, activation of retinal glial cells, and photoreceptor cell loss by 8 months of age. The development of these changes is accelerated by inoculation with brain homogenate from clinically ill TgM83 mice. Compared to non-inoculated 5-month-old TgM83 mice, retinas of inoculated 5-month-old mice had increased accumulation of alpha-synuclein (pSer129) and pTauThr231 proteins, upregulated microglial activation, and dysregulated macroautophagy. Raman spectroscopic analysis was able to discriminate between healthy and diseased mice. This study describes retinal pathology resulting from the A53T mutation. We show that seeding with brain homogenates from old TgM83 mice accelerates retinal pathology. We demonstrate that Raman spectroscopy can be used to accurately identify a diseased retina based on its biochemical profile, and that alpha-synuclein accumulation may contribute to accumulation of pTauThr231 proteins, neuroinflammation, metabolic dysregulation, and photoreceptor cell death. Our work provides insight into retinal changes associated with Parkinson's disease, and may contribute to a better understanding of visual symptoms experienced by patients.