Accelerated accumulation of retinal alpha-synuclein (pSer129) and tau, neuroinflammation, and autophagic dysregulation in a seeded mouse model of Parkinson's disease

Authors: MAMMADOVA, NAJIBA - Iowa State University; SUMMERS, COREY - Iowa State University; Kokemuller, Robyn; HE, QING - Iowa State University; DING, SHAOWEI - Iowa State University; BARON, THIERRY - French Agency For Food, Environmental And Occupational Health & Safety (ANSES); YU, CHENXU - Iowa State University; VALENTINE, RUDY - Iowa State University; SAKAGUCHI, DONALD - Iowa State University; KANTHASAMY, A - Iowa State University; Greenlee, Justin; WEST GREENLEE, M - Iowa State University

Submitted to: Neurobiology of Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/11/2018
Publication Date: 1/1/2019
Citation: Mammadova, N., Summers, C.M., Kokemuller, R.D., He, Q., Ding, S., Baron, T., Yu, C., Valentine, R.J., Sakaguchi, D.S., Kanthasamy, A.G., Greenlee, J.J., West Greenlee, M.H. 2019. Accelerated accumulation of retinal alpha-synuclein (pSer129) and tau, neuroinflammation, and autophagic dysregulation in a seeded mouse model of Parkinson's disease. Neurobiology of Disease. 121:1-16. https://doi.org/10.1016/j.nbd.2018.09.013.
DOI: https://doi.org/10.1016/j.nbd.2018.09.013

Interpretive Summary: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of a misfolded protein called alpha-synuclein within the central nervous system (CNS). Accumulation of misfolded proteins in the CNS is a theme in other neurodegenerative disease such as prion diseases (prion protein) and Alzheimer's disease (tau and beta-amyloid proteins). Previously, our group has shown that changes of the visual system (retina) and visual deficits occur during the progression of prion disease in mice, sheep, and cattle. While visual problems are common in human patients with Parkinson's disease, associated retinal changes are not well understood. This work uses a transgenic mouse model of Parkinson's disease to demonstrate retinal changes including inflammation, loss of cellular maintenance, and cell death. A major finding of this work is the successful application of Raman spectroscopy, a method of classifying the biochemical signature of a tissue, to differentiate between retinas from healthy and diseased animals. Raman spectroscopy of the retina has the potential for use as a live-patient diagnostic for Parkinson's or other protein misfolding disease such as prion diseases. This is the first to characterize retinal changes associated with Parkinson's disease and to use Raman spectroscopy to classify retinal tissues in a study of neurodegenerative disease. Next steps for this work will be Raman characterization of tissues from animals with prion diseases and to assess live animals. This information has the potential to be high impact to professionals in the fields of human or animal health where currently available diagnostic tests for neurodegenerative diseases are notoriously poor.

Technical Abstract: Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by accumulation of misfolded alpha-synuclein within the central nervous system (CNS). 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 mutated a-synuclein, and assess the effect of alpha-synuclein "seeding" on the development of retinal pathology. Methods: Two-month-old TgM83 mice were intracerebrally inoculated with brain homogenate from old (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, pTau*Thr231, inflammation, changes in macroautophagy, and cell death. Raman spectroscopy was used to test the potential to differentiate between retinal tissues of healthy mice and those carrying an alpha-synuclein mutation. Results: This work shows 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 pTau*Thr231 proteins, upregulated microglial activation, and dysregulated macroautophagy. Raman Spectroscopic analysis was used to discriminate between healthy and diseased mice. Conclusions: 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 analysis can be used to accurately identify a diseased retina based on a biochemical profile, and that alpha-synuclein may contribute to accumulation of pTau*Thr231 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.