Abstract
BackgroundIt has been widely established that the conversion of the cellular prion protein (PrPC) into its abnormal isoform (PrPSc) is responsible for the development of transmissible spongiform encephalopathies (TSEs). However, the knowledge of the detailed molecular mechanisms and direct functional consequences within the cell is rare. In this study, we aimed at the identification of deregulated proteins which might be involved in prion pathogenesis.FindingsApolipoprotein E and peroxiredoxin 6 (PRDX6) were identified as upregulated proteins in brains of scrapie-infected mice and cultured neuronal cell lines. Downregulation of PrP gene expression using specific siRNA did not result in a decrease of PRDX6 amounts. Interestingly, selective siRNA targeting PRDX6 or overexpression of PRDX6 controlled PrPC and PrPSc protein amounts in neuronal cells.ConclusionsBesides its possible function as a novel marker protein in the diagnosis of TSEs, PDRX6 represents an attractive target molecule in putative pharmacological intervention strategies in the future.
Highlights
It has been widely established that the conversion of the cellular prion protein (PrPC) into its abnormal isoform (PrPSc) is responsible for the development of transmissible spongiform encephalopathies (TSEs)
The molecular hallmark of these disorders is a structural conversion in folding of the normal cellular prion protein (PrPC) into a disease-associated, proteaseresistant isoform (PrPSc) [2]
Neuropathological characteristics of these diseases include neuronal loss, vacuolar degeneration, astrogliosis and amyloid plaque formation caused by accumulation of PrPSc [3]
Summary
Besides its possible function as a novel marker protein in the diagnosis of TSEs, PDRX6 represents an attractive target molecule in putative pharmacological intervention strategies in the future. PRDX6 protein expression in astrocytes has already been associated with Alzheimer disease where it might function as an antioxidant enzyme [9] suggesting that PRDX6 might be involved in neurological diseases To investigate this in more detail, we followed PRDX6 expression during scrapie infection in mice and compared it with PRDX1-4 amounts by Western blot analyses (Figure 1C). N2a58# cells was slightly decreased and PK-resistant PrPSc was strongly reduced in N2a58/22L upon siRNA treatment to inhibit PRXD6 expression (Figure 3C) These data led to the suggestion that there is a functional connection between PrP and PRDX6 expression.
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