Study on changes of endogenous metabolites in olfactory bulb of early⁃stage Parkinson's disease induced by SNCA gene Ala53Thr base substitution in mice

Abstract

Objective To explore the pathophysiologic mechanism of SNCA gene in the early⁃stage of Parkinson's disease (PD). Methods Wild type (WT group, n=10) and SNCA Ala53Thr base substitution mice (TG group, n=10) were selected for further experiments. Endogenous metabolites in olfactory bulb (OB) of transgenic and wild type mice were detected and analyzed by high performance liquid chromatography⁃tandem mass spectrometry (HPLC⁃MS/MS). Then the endogenous metabolites were identified through mzCloud and determined by molecular formula and molecular weight. The differential endogenous metabolites were obtained by principal component analysis (PCA), partial least squares discrimination analysis (PLS⁃DA), orthogonal partial least squares discriminant analysis (OPLS⁃DA) and cluster analysis. Finally, the pathway and interaction network between the differential endogenous metabolites and corresponding pathways were constructed. Results Finally 29 variations were identified as differential metabolites. Among them, the relative expressions of phosphatidylcholine (PC), phosphatidylethanolamine (PE), vitamin C, sphingomyelin (SM), phosphatidylglycerol (PG) and glutamic acid were elevated in TG group (P＜0.05, for all) and the negative relationship was shown between elevated metabolite and decreased metabolite in relative expression, while the relative expressions of phosphalipids, taurine, ceramide valine and γ⁃aminobutyric acid (GABA) were decreased in TG group (P＜0.05, for all) and the relationship of relative expression among them was positive. The related metabolic pathways were mainly associated with the taurine and hypotaurine metabolism, glutamine and glutamate metabolism, ascorbate and aldarate metabolism, glycerophospholipid metabolism and alanine, aspartate and glutamate metabolism, included taurine, D⁃glutamate, vitamine C, phospholipid, LysoPC [18: 2 (9Z, 12Z)] and GABA all 6 significant metabolites. Conclusions The experiment verified pathological changes of OB in the early stage of PD. Meanwhile the differences in phosphatides could be a direct result of SNCA Ala53Thr mutation. Furthermore, malfunction of neurons in OB is also observed and may be contributed to the abnormal phosphatides' metabolism.

Keywords

• parkinson disease
• alpha⁃synuclein
• genes
• mutation
• metabolomics
• olfactory bulb
• chromatography
• liquid