Abstract
Prion diseases are transmissible spongiform encephalopathies induced by the abnormally-folded prion protein (PrPSc), which is derived from the normal prion protein (PrPC). Previous studies have reported that lipid rafts play a pivotal role in the conversion of PrPC into PrPSc, and several therapeutic strategies targeting lipids have led to prolonged survival times in prion diseases. In addition, phosphatidylethanolamine, a glycerophospholipid member, accelerated prion disease progression. Although several studies have shown that prion diseases are significantly associated with lipids, lipidomic analyses of prion diseases have not been reported thus far. We intraperitoneally injected phosphate-buffered saline (PBS) or ME7 mouse prions into mice and sacrificed them at different time points (3 and 7 months) post-injection. To detect PrPSc in the mouse brain, we carried out western blotting analysis of the left hemisphere of the brain. To identify potential novel lipid biomarkers, we performed lipid extraction on the right hemisphere of the brain and liquid chromatography mass spectrometry (LC/MS) to analyze the lipidomic profiling between non-infected mice and prion-infected mice. Finally, we analyzed the altered lipid-related pathways by a lipid pathway enrichment analysis (LIPEA). We identified a total of 43 and 75 novel potential biomarkers at 3 and 7 months in prion-infected mice compared to non-infected mice, respectively. Among these novel potential biomarkers, approximately 75% of total lipids are glycerophospholipids. In addition, altered lipids between the non-infected and prion-infected mice were related to sphingolipid, glycerophospholipid and glycosylphosphatidylinositol (GPI)-anchor-related pathways. In the present study, we found novel potential biomarkers and therapeutic targets of prion disease. To the best of our knowledge, this study reports the first large-scale lipidomic profiling in prion diseases.
Highlights
Prion diseases are fatal and irreversible neurodegenerative disorders caused by the abnormally folded prion protein (PrPSc), which originates from the normal prion protein (PrPC) [1,2,3,4,5,6]
Several studies have suggested that lipids are significantly related to the conversion process of Abnormal prion protein (PrPSc), lipidomic profiling has not been reported in prion diseases far
In the present study, we did not detect PrPSc in ME7 scrapie-injected mice at 3 months (Figure 1B), global lipidomic changes were found in the early stage of prion disease (Figure 4)
Summary
Prion diseases are fatal and irreversible neurodegenerative disorders caused by the abnormally folded prion protein (PrPSc), which originates from the normal prion protein (PrPC) [1,2,3,4,5,6]. PrPC is located in lipid rafts via Previous studies have reported that the lipid raft, which consists of glycosphingolipids, cholesterol and protein receptors organized in lipid microdomains, is critically associated with the conformational conversion process of. An in vitro prion disease model showed impaired cholesterol metabolism, and the reduction in cellular cholesterol levels by lovastatin, filipin and squalestatin contributed to diminishing PrPSc formation [15,16,17,18]. A recent study reported that phosphatidylethanolamine acts as an independent cofactor for in vitro P rPSc formation in the absence of genetic materials [21]. Several studies have suggested that lipids are significantly related to the conversion process of PrPSc, lipidomic profiling has not been reported in prion diseases far
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