|Greenlee, M. Heather West|
Submitted to: Journal of Comparative Pathology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/10/2007
Publication Date: 1/1/2008
Citation: Smith, J.D., Greenlee, J.J., Hamir, A.N., West Greenlee, M.H. 2008. Retinal cell types are differentially affected in sheep with scrapie. Journal of Comparative Pathology. 138(1):12-22. Interpretive Summary: Scrapie is a naturally occurring fatal disease of sheep and goats affecting the nervous system. After infection, the scrapie agent is known to accumulate in the brain, lymph nodes, and retina, the specialized sensory structure lining the inside of the eye. All current methods of diagnosis for scrapie and related diseases require collection of brain tissue after death of the animal. This study uses special staining techniques to show that accumulation of the agent causing scrapie in sheep is associated with altered staining patterns in certain subtypes of retinal cells. Each cell type in the retina has a specific function and alters ophthalmologic examinations or electrophysiologic tests in predictable ways when damaged. These findings increase the current understanding of how abnormal prion proteins accumulate in the cells of the nervous system (retina), but more importantly suggest that methods of identifying scrapie-affected animals through functional testing of the visual system can be developed.
Technical Abstract: Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases characterized microscopically by spongiform lesions (vacuolation) in the neuropil, neuronal loss, and gliosis. Although it has been suggested that normal neuronal morphology may be altered in TSE cases prior to the appearance of obvious microscopic lesions, evidence of prior subcellular morphological disruption is lacking. The retina offers an accessible, highly organized, rostral extension of the brain with well-characterized cellular phenotypes, making it well suited for studying alterations of cellular morphology and synaptic connectivity in the CNS. Accumulation of PrP**Sc has been demonstrated in the retina of natural and non-natural TSE-affected hosts, with or without evidence of microscopically detectable retinal pathology. To investigate the effect of PrP**Sc accumulation on the morphology of retinal neurons in a natural host, we used immunohistochemistry to examine the distribution of various retinal cell type-specific markers in the retinas of control sheep, and scrapie-affected sheep with varying degrees of retinal PrP**Sc accumulation. In retinas with PrP**Sc-immunoreactivity (-IR), we observed disruption of the normal -IR patterns of the alpha isoform of protein kinase C (PKC-alpha) and vesicular glutamate transporter 1 (VGLUT1), markers of retinal bipolar cells. Altered -IR patterns were also observed for microtubule-associated protein 2 (MAP2), a marker of a subset of retinal ganglion cells, and glutamine synthetase (GS), a marker of Müller glia. These results demonstrate morphologic changes are present in specific cell types in retinas with PrP**Sc accumulation, despite an absence of overt histologic lesions consistent with retinal degeneration.