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ARS Home » Midwest Area » Ames, Iowa » National Animal Disease Center » Virus and Prion Research » Research » Publications at this Location » Publication #337276

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

Location: Virus and Prion Research

Title: Accumulation of phosphorylated alpha-synuclein (p129S) and retinal pathology in a mouse model of Parkinson's disease

item MAMMADOVA, NAJIBA - Iowa State University
item Kokemuller, Robyn
item SAKAGUCHI, DONALD - Iowa State University
item BARON, THIERRY - French Agency For Food, Environmental And Occupational Health & Safety (ANSES)
item Greenlee, Justin
item KANTHASAMY, ANUMANTHA - Iowa State University
item WEST GREENLEE, M - Iowa State University

Submitted to: Prion
Publication Type: Abstract Only
Publication Acceptance Date: 3/15/2017
Publication Date: N/A
Citation: N/A

Interpretive Summary:

Technical Abstract: Aims: Parkinson's disease (PD) is a neurodegenerative disorder characterized by accumulation of misfolded alpha-synuclein within the CNS. Although non-motor clinical phenotypes of PD such as visual dysfunction have become increasingly apparent, retinal pathology associated with PD is not well understood. In this study, we use immunohistochemistry to study the progression of retinal pathology in a transgenic mouse model (TgM83) expressing the human A53T mutated alpha-synuclein. Furthermore, TgM83 mice were intracerebrally (IC) inoculated with brain homogenates from TgM83 mice showing motor clinical signs. This resulted in decreased survival time, as well as acceleration of brain pathology. Mice showed early motor signs of disease, and intracellular aggregates of alpha-synuclein. The purpose of this study was to investigate the effect of alpha-synuclein "seeding" or propagation throughout the CNS, on retinal pathology. Methods: Homozygous TgM83 mice were IC inoculated with 20 µL of 1% (wt/vol in glucose 5%) brain homogenates from clinically ill TgM83 mice (12-18 months). Controls included: uninoculated TgM83 mice; and B6C3H mice (genetic background of the TgM83 mouse model). We assessed retinal tissues using immunofluorescence for phosphorylated alpha-synuclein (pSer129), tyrosine hydroxylase TH (specific to dopaminergic amacrine cells in the retina), glial fibrillary acidic protein (GFAP), microglia specific proteins (Iba1 and CD68), phospho-tau (pThr231), and calbindin (specific to horizontal cells in the retina). Results: Retinas of uninoculated TgM83 mice showed activation of Müller glia and microglia, loss of photoreceptor cells, and accumulation of phosphorylated alpha-synuclein (pSer129). We observed accumulation of phospho-tau (pThr231) in Müller glia and astrocytes, and horizontal cells. Inoculation with brain homogenate, resulted in acceleration of retinal pathology. Compared to non-inoculated – TgM83 mice, we show increased Iba1, and CD68 immunoreactivity (~2.5 fold; ~3 fold increase respectively); and phospho-tau (pThr231) (7 fold increase) in retinas of inoculated mice. Acceleration of GFAP immunoreactivity, or photoreceptor cell loss was not detected. Conclusions: Our results show specific pathologies associated with the A53T mutation. Moreover, our work suggests that inoculation, or seeding with brain homogenates from old and sick TgM83 mice accelerates retinal pathology. Accumulation of misfolded alpha-synuclein may preferentially accelerate specific retinal pathologies such as activation of microglia, and accumulation of pre-tangle phospho-tau (Thr231) in retinal neurons and glia. Activation of Müller glia, and loss of photoreceptor cells due to disease progression does not seem to be affected by alpha-synuclein seeding. Our work provides insight into the effect of Parkinson's disease on the retina, and may contribute to a better understanding of visual symptoms experienced by patients.