Alterations in neuronal metabolism contribute to the pathogenesis of prion disease

Abstract

Neurodegenerative conditions are characterised by a progressive loss of neurons, which is believed to be initiated by misfolded protein aggregations. During this time period, many physiological and metabolomic alterations and changes in gene expression contribute to the decline in neuronal function. However, these pathological effects have not been fully characterised. In this study, we utilised a metabolomic approach to investigate the metabolic changes occurring in the hippocampus and cortex of mice infected with misfolded prion protein. In order to identify these changes, the samples were analysed by ultrahigh-performance liquid chromatography-tandem mass spectroscopy. The present dataset comprises a total of 498 compounds of known identity, named biochemicals, which have undergone principal component analysis and supervised machine learning. The results generated are consistent with the prion-inoculated mice having significantly altered metabolic profiles. In particular, we highlight the alterations associated with the metabolism of glucose, neuropeptides, fatty acids, L-arginine/nitric oxide and prostaglandins, all of which undergo significant changes during the disease. These data provide possibilities for future studies targeting and investigating specific pathways to better understand the processes involved in neuronal dysfunction in neurodegenerative diseases.

Inhibition of neuroinflammatory nitric oxide signalling supresses protein glycation and recovers neuronal dysfunction in prion disease

“…(P=0.0039, control NBH vs RML mice, Student's t-test, Fig. 5a) providing evidence for enhanced oxidative stress as one hallmark of the disease and confirming previously reported increases in oxidative stress levels in prion-diseased mice [8]. Together with the enhanced levels of nitrergic stress associated with augmented expression levels of iNOS mRNA (Fig.…”

“…We have previously shown that NBH mice lack any significant NADPH diaphorase signals at 10 w.p.i. [8]. This data illustrates a strong increase of NOS (NADPH activity) from 8 w.p.i.…”

“…Previously we have found that in the hippocampus and cortex of prion infected mice the neuronal metabolism, not only related to the NO signalling cascade, is aberrantly regulated at 10 w.p.i. [8]. At this advanced time point we found evidence for numerous pathological markers such as high levels of misfolded prion protein (PrP Sc ) in the hippocampus and cortex, enhanced glial fibrillary acidic protein (GFAP) expression associated with nitrergic and oxidative stress, and hippocampal neuronal loss as well as learning and memory deficits [37,41].…”

“…). Excessive NO production reported in prion disease, AD and PD is leading to aberrant post-translational protein modifications and unbalanced neurotoxic nitrergic signalling [6][7][8][9]. Protein cysteine residues can be directly and reversibly S-nitrosylated by NO [9] which can lead to protein dysfunction to facilitate disease progression [10,11].…”

“…The platform used by Metabolon integrates the chemical analysis, including identification and relative quantification, data reduction, and quality assurance components of the process. Workflow including extraction of raw data, peak-identification, and quality control processed on the assay platform, has been described previously [8].…”