Ion-current-based Proteomic Profiling of the Retina in a Rat Model of Smith-Lemli-Opitz Syndrome *
Molecular & Cellular Proteomics, ISSN: 1535-9476, Vol: 12, Issue: 12, Page: 3583-3598
2013
- 47Citations
- 26Captures
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Metrics Details
- Citations47
- Citation Indexes47
- CrossRef47
- 47
- Captures26
- Readers26
- 26
Article Description
Smith-Lemli-Opitz syndrome (SLOS) is one of the most common recessive human disorders and is characterized by multiple congenital malformations as well as neurosensory and cognitive abnormalities. A rat model of SLOS has been developed that exhibits progressive retinal degeneration and visual dysfunction; however, the molecular events underlying the degeneration and dysfunction remain poorly understood. Here, we employed a well-controlled, ion-current-based approach to compare retinas from the SLOS rat model to retinas from age- and sex-matched control rats ( n = 5/group). Retinas were subjected to detergent extraction and subsequent precipitation and on-pellet-digestion procedures and then were analyzed on a long, heated column (75 cm, with small particles) with a 7-h gradient. The high analytical reproducibility of the overall proteomics procedure enabled reliable expression profiling. In total, 1,259 unique protein groups, ∼40% of which were membrane proteins, were quantified under highly stringent criteria, including a peptide false discovery rate of 0.4%, with high quality ion-current data ( e.g. signal-to-noise ratio ≥ 10) obtained independently from at least two unique peptides for each protein. The ion-current-based strategy showed greater quantitative accuracy and reproducibility over a parallel spectral counting analysis. Statistically significant alterations of 101 proteins were observed; these proteins are implicated in a variety of biological processes, including lipid metabolism, oxidative stress, cell death, proteolysis, visual transduction, and vesicular/membrane transport, consistent with the features of the associated retinal degeneration in the SLOS model. Selected targets were further validated by Western blot analysis and correlative immunohistochemistry. Importantly, although photoreceptor cell death was validated by TUNEL analysis, Western blot and immunohistochemical analyses suggested a caspase-3- independent pathway. In total, these results provide compelling new evidence implicating molecular changes beyond the initial defect in cholesterol biosynthesis in this retinal degeneration model, and they might have broader implications with respect to the pathobiological mechanism underlying SLOS.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S1535947620338263; http://dx.doi.org/10.1074/mcp.m113.027847; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84890574613&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/23979708; https://linkinghub.elsevier.com/retrieve/pii/S1535947620338263; http://www.mcponline.org/lookup/doi/10.1074/mcp.M113.027847; https://syndication.highwire.org/content/doi/10.1074/mcp.M113.027847; https://dx.doi.org/10.1074/mcp.m113.027847; http://www.mcponline.org/cgi/doi/10.1074/mcp.M113.027847; https://www.mcponline.org/content/12/12/3583; https://www.mcponline.org/content/12/12/3583.abstract; https://www.mcponline.org/content/mcprot/12/12/3583.full.pdf; http://www.mcponline.org/content/12/12/3583; http://www.mcponline.org/content/12/12/3583.abstract; http://www.mcponline.org/content/12/12/3583.full.pdf
Elsevier BV
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