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

dc.contributor.author Mammadova, Najiba
dc.contributor.author Summers, Corey
dc.contributor.author Yu, Chenxu
dc.contributor.author Kokemuller, Robyn
dc.contributor.author He, Qing
dc.contributor.author Ding, Shaowei
dc.contributor.author Baron, Thierry
dc.contributor.author Valentine, Rudy
dc.contributor.author Sakaguchi, Donald
dc.contributor.author Kanthasamy, Anumantha
dc.contributor.author Greenlee, Justin
dc.contributor.author West Greenlee, M. Heather
dc.contributor.department Department of Biomedical Sciences
dc.contributor.department Mechanical Engineering
dc.contributor.department Immunobiology Interdepartmental Graduate Program
dc.contributor.department Neuroscience
dc.contributor.department Department of Kinesiology
dc.contributor.department Department of Genetics, Development, and Cell Biology (LAS)
dc.contributor.department Department of Agricultural and Biosystems Engineering (ENG)
dc.contributor.department Environmental Science
dc.date 2019-09-08T15:47:06.000
dc.date.accessioned 2020-06-29T22:36:24Z
dc.date.available 2020-06-29T22:36:24Z
dc.date.issued 2019-01-01
dc.description.abstract <p>Parkinson's disease (PD) is a neurodegenerative disorder characterized by accumulation of misfolded α-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 α-synuclein mutation and assess the effect of α-synuclein “seeding” on the development of retinal pathology. 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 α-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 α-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 α-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 α-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.</p>
dc.description.comments <p>This article is published as Mammadova, Najiba, Corey M. Summers, Robyn D. Kokemuller, Qing He, Shaowei Ding, Thierry Baron, Chenxu Yu, Rudy J. Valentine, Donald S. Sakaguchi, Anumantha G. Kanthasamy, Justin J. Greenlee, and M. Heather West Greenlee. "Accelerated accumulation of retinal α-synuclein (pSer129) and tau, neuroinflammation, and autophagic dysregulation in a seeded mouse model of Parkinson's disease." <em>Neurobiology of Disease</em> 121 (2019): 1-16. DOI: <a href="http://dx.doi.org/10.1016/j.nbd.2018.09.013" target="_blank">10.1016/j.nbd.2018.09.013</a>. </p>
dc.format.mimetype application/pdf
dc.identifier archive/lib.dr.iastate.edu/abe_eng_pubs/1039/
dc.identifier.articleid 2323
dc.identifier.contextkey 14900147
dc.identifier.s3bucket isulib-bepress-aws-west
dc.identifier.submissionpath abe_eng_pubs/1039
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/739
dc.language.iso en
dc.source.bitstream archive/lib.dr.iastate.edu/abe_eng_pubs/1039/2019_YuChenxu_AcceleratedAccumulation.pdf|||Fri Jan 14 18:19:48 UTC 2022
dc.source.uri 10.1016/j.nbd.2018.09.013
dc.subject.disciplines Disease Modeling
dc.subject.disciplines Molecular Genetics
dc.subject.disciplines Nervous System Diseases
dc.subject.disciplines Neuroscience and Neurobiology
dc.subject.keywords Retina in Parkinson's Disease
dc.subject.keywords Photoreceptor cell loss
dc.subject.keywords Tau in retina
dc.subject.keywords Microglial activation in retina
dc.subject.keywords Müller glial activation
dc.subject.keywords Misfolded α-synuclein
dc.subject.keywords Human A53T mutated α-synuclein
dc.subject.keywords Autophagy in PD retina
dc.subject.keywords Raman Spectroscopy
dc.title Accelerated accumulation of retinal α-synuclein (pSer129) and tau, neuroinflammation, and autophagic dysregulation in a seeded mouse model of Parkinson's disease
dc.type article
dc.type.genre article
dspace.entity.type Publication
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