Abstract
Hepatic encephalopathy (HE) is a neurological disease associated with hepatic dysfunction. Current knowledge suggests that hyperammonemia, related to liver failure, is a main factor contributing to the cerebral alterations in HE and that hyperammonemia might impair signal transduction associated with post-translational modification of proteins such as tyrosine-nitration and phosphorylation. However, the molecular bases of the HE remain unclear and very little is known about the occurrence of post-translational modification on in vivo proteins. In this exploratory study we look for evidence of post-translation modifications of proteins in the cerebellum of experimental HE rat models using a proteomic approach. For the first time we showed that hyperammonemia without liver failure (HA rats) and experimental HE with liver failure due to portacaval shunt (PCS rats) lead to a reduced protein nitration in rat cerebellum, where the undernitrated proteins were involved in energy metabolism and cytoskeleton remodelling. Moreover we showed that tyrosine nitration loss of these proteins was not necessarily associated to a change in their phosphorylation state as result of the disease. Interestingly the rat cerebellum phosphoproteome was mainly perturbed in PCS rats, whereas HA rats did not shown appreciable changes in their phosphoprotein profile. Since the protein nitration level decreased similarly in the cerebellum of both HA and PCS rats, this implies that the two disease models share common effects but also present some differential signalling effects in the cerebellum of the same animals. This study highlights the interest for studying the concerted action of multiple signalling pathways in HE development.
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Acknowledgement
This work was supported by grants from Ministerio de Ciencia Innovacion (SAF2008-00062, CSD2008-00005) of Spain and from Conselleria de Educacion (ACOMP-2009-025; PROMETEO/2009/027; ACOMP-2010-220) and Conselleria de Sanitat (AP-024/08, AP-092/09; AP-043/10) of Generalitat Valenciana.
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Table S1
Submission parameters for the identification of nitrated proteins (DOC 39 kb)
Table S2
Submission parameters for the identification of phosphorylated proteins (DOC 39 kb)
Table S3
Proteins and petides identification_nitrated proteins (XLS 82 kb)
Table S4
Proteins and peptides identification_phopshorylated proteins (XLS 72 kb)
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Brunelli, L., Campagna, R., Airoldi, L. et al. Exploratory investigation on nitro- and phospho-proteome cerebellum changes in hyperammonemia and hepatic encephalopathy rat models. Metab Brain Dis 27, 37–49 (2012). https://doi.org/10.1007/s11011-011-9268-4
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DOI: https://doi.org/10.1007/s11011-011-9268-4