Abstract
Parkinson’s disease (PD) is considered a synucleinopathy because of the intraneuronal accumulation of aggregated α-synuclein (αSyn). Recent evidence points to soluble αSyn-oligomers (αSynO) as the main cytotoxic species responsible for cell death. Given the pivotal role of αSyn in PD, αSyn-based models are crucial for the investigation of toxic mechanisms and the identification of new therapeutic targets in PD. By using a metabolomics approach, we evaluated the metabolic profile of brain and serum samples of rats infused unilaterally with preformed human αSynOs (HαSynOs), or vehicle, into the substantia nigra pars compacta (SNpc). Three months postinfusion, the striatum was dissected for striatal dopamine (DA) measurements via High Pressure Liquid Chromatography (HPLC) analysis and mesencephalon and serum samples were collected for the evaluation of metabolite content via gas chromatography mass spectrometry analysis. Multivariate, univariate and correlation statistics were applied. A 40% decrease of DA content was measured in the HαSynO-infused striatum as compared to the contralateral and the vehicle-infused striata. Decreased levels of dehydroascorbic acid, myo-inositol, and glycine, and increased levels of threonine, were found in the mesencephalon, while increased contents of fructose and mannose, and a decrease in glycine and urea, were found in the serum of HαSynO-infused rats. The significant correlation between DA and metabolite content indicated that metabolic variations reflected the nigrostriatal degeneration. Collectively, the metabolomic fingerprint of HαSynO-infused rats points to an increase of oxidative stress markers, in line with PD neuropathology, and provides hints for potential biomarkers of PD.
Highlights
Abnormal aggregation of specific pathogenic proteins within the central nervous system has been recognized as a fundamental feature of several neurodegenerative disorders, including Parkinson’s disease (PD) [1]
We found that the intracerebral inoculation of these human αSynOs (HαSynOs) induced a gradual nigrostriatal dopaminergic loss associated with motor and cognitive impairment, the deposition of phosphorylated αSyn in neurons and microglia of dopaminergic areas, an early and persistent neuroinflammatory response and mitochondrial abnormalities, suggesting that it is a valuable preclinical model of PD that reproduces the cardinal features of the pathology [unpublished results]
Gas chromatography mass spectrometry (GC-MS) analysis performed on tissue from the right and left mesencephalon and on serum from rats (n = 7) inoculated with HαSynOs into the left substantia nigra pars compacta (SNpc) (Oligo class, Right (R) and Left (L), respectively) or with vehicle (n = 7) (Veh class, Right (R) and Left (L), respectively) showed significant metabolic changes in the inoculated rats compared with vehicles, and a correlation with striatal dopamine (DA) content
Summary
Abnormal aggregation of specific pathogenic proteins within the central nervous system has been recognized as a fundamental feature of several neurodegenerative disorders, including Parkinson’s disease (PD) [1]. Preformed αSyn oligomers of human origin (HαSynO) have been produced and characterized for their in vitro and in vivo toxicity in neurons [7,16]. These studies demonstrated that these short oligomers hold a higher neurotoxicity compared to the monomeric species of the protein. We found that the intracerebral inoculation of these HαSynOs induced a gradual nigrostriatal dopaminergic loss associated with motor and cognitive impairment, the deposition of phosphorylated αSyn in neurons and microglia of dopaminergic areas, an early and persistent neuroinflammatory response and mitochondrial abnormalities, suggesting that it is a valuable preclinical model of PD that reproduces the cardinal features of the pathology [unpublished results]
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