Degree Type

Dissertation

Date of Award

2019

Degree Name

Doctor of Philosophy

Department

Genetics, Development and Cell Biology

Major

Immunobiology; Neuroscience

First Advisor

Mary H. West Greenlee

Second Advisor

Donald S. Sakaguchi

Abstract

Retinal manifestations have been described in several neurodegenerative insults and disorders. The strong similarities between the retina and the brain and the accessibility of the retina has potentiated studies to investigate retinal pathology in an effort to identify biomarkers for early diagnosis, as well as for monitoring the progression of disease and efficacy of therapies as they become available. However, there is a limited understanding of retinal pathological landmarks of disease progression.

In the studies conducted in this dissertation, we investigate retinal changes associated with ocular blast injury, and protein-misfolding - in a mouse model of Parkinsonism, and in bovine spongiform encephalopathy (BSE), a transmissible spongiform encephalopathy (TSE) that affects cattle. Our work demonstrates that a neurodegenerative insult, specifically exposure to blast wave pressure, results in lasting retinal changes – activation of Mϋller glia, astrocytes and microglia, accumulation of phospho-tau species, and photoreceptor cell loss – that was not detected in the brain. Additionally, we report retinal changes associated with the burden of misfolded protein accumulation. Studies conducted using a transgenic mouse model of PD (TgM83, expressing human α-synuclein containing the familial PD-associated A53T mutation) demonstrate that the spread of α-synuclein and subsequent deposition in the retina may contribute to accumulation of phosphorylated tau proteins, neuroinflammation, metabolic dysregulation, and photoreceptor cell death. Additionally, we reported that Raman spectroscopy, an imaging technique that measures scattered light, can be used to accurately distinguish diseased retinal tissue from healthy retinal tissues based on their biochemical profile. Finally, we report that due to the similarities between TSEs and other protein misfolding diseases, TSEs can be used to understand other proteinopathies. In this study, we used the differences in incubation period (the time from inoculation to the appearance of unequivocal clinical signs of disease) between classical and atypical BSEs as a model to identify the molecular factors associated with disease progression in the retina. We demonstrate that atypical BSEs, characterized by shorter incubation periods, have greater accumulation of misfolded prion protein (PrPSc), retinal glial-cell activation, neuroinflammation, and decreased autophagy. This work described a relationship between disease incubation period, neuroinflammation, and the autophagic stress response, that was previously unknown. Overall, this work provides insight into retinal changes associated with injury and protein-misfolding, and may contribute to the identification of early retinal biomarkers of disease progression and development of corresponding therapies.

Copyright Owner

Najiba Mammadova

Language

en

File Format

application/pdf

File Size

172 pages

Share

COinS