Biochemical Profiling of the Brain and Blood Metabolome in a Mouse Model of Prodromal Parkinson’s Disease Reveals Distinct Metabolic Profiles

Abstract

Parkinson's disease is the second most common neurodegenerative disease. In the vast majority of cases the origin is not genetic and the cause is not well understood, although progressive accumulation of α-synuclein aggregates appears central to the pathogenesis. Currently, treatments that slow disease progression are lacking, and there are no robust biomarkers that can facilitate the development of such treatments or act as aids in early diagnosis. Therefore, we have defined metabolomic changes in the brain and serum in an animal model of prodromal Parkinson's disease. We biochemically profiled the brain tissue and serum in a mouse model with progressive synucleinopathy propagation in the brain triggered by unilateral injection of preformed α-synuclein fibrils in the olfactory bulb. In total, we accurately identified and quantified 71 metabolites in the brain and 182 in serum using H NMR and targeted mass spectrometry, respectively. Using multivariate analysis, we accurately identified which metabolites explain the most variation between cases and controls. Using pathway enrichment analysis, we highlight significantly perturbed biochemical pathways in the brain and correlate these with the progression of the disease. Furthermore, we identified the top six discriminatory metabolites and were able to develop a model capable of identifying animals with the pathology from healthy controls with high accuracy (AUC (95% CI) = 0.861 (0.755-0.968)). Our study highlights the utility of metabolomics in identifying elements of Parkinson's disease pathogenesis and for the development of early diagnostic biomarkers of the disease.

Metabolomics analysis of the hippocampus in a rat model of traumatic brain injury during the acute phase

“…Additionally, ornithine was associated with cognitive impairment and was also found in plasma metabolomics profiles in acute TBI rats (Fei et al, 2017;Wu et al, 2014). In the case of taurine and hypotaurine metabolism, the pathway enrichment analysis suggested its dysregulation in Alzheimer's disease and the development of perturbed markers in Parkinson's disease (Graham et al, 2018;Gui, Liu, Zhang, Lv, & Hu, 2015). Conversely, the results from (Menzie, Prentice, & Wu, 2013) and (Wen et al, 2018) highlighted that taurine and hypotaurine metabolism can protect neurons against inflammatory response or may be related to hypoxic preconditioning.…”

Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

“…Currently, a novel approach towards the utilization of bile acids in PD is being considered. Since, to date, no reliable biomarkers of PD exist, Graham et al investigated alterations in bile acid profiles as potential biomarkers used in early diagnosis of PD [129,148]. In this respect, prodromal mouse model of PD was used to measure serum concentrations of 18 bile acids.…”

Metabolomic Profiling of Bile Acids in an Experimental Model of Prodromal Parkinson’s Disease

“…In a previous study by our group, we identified Bile Acid metabolism as one of the major biochemical pathways to be perturbed in the brain of a mouse model of prodromal PD [10]. Bile acids are molecules derived from cholesterol in hepatocytes and are used to emulsify fats in the small intestine and promote fat digestion and absorption [11,12].…”