Major Alterations of Phosphatidylcholine and Lysophosphotidylcholine Lipids in the Substantia Nigra Using an Early Stage Model of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal pathway, where patients do not manifest motor symptoms until >50% of neurons are lost. Thus, it is of great importance to determine early neuronal changes that may contribute to disease progression. Recent attention has focused on lipids and their role in pro- and anti-apoptotic processes. However, information regarding the lipid alterations in animal models of PD is lacking. In this study, we utilized high performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) and novel HPLC solvent methodology to profile phosphatidylcholines and sphingolipids within the substantia nigra. The ipsilateral substantia nigra pars compacta was collected from rats 21 days after an infusion of 6-hydroxydopamine (6-OHDA), or vehicle into the anterior dorsal striatum. We identified 115 lipid species from their mass/charge ratio using the LMAPS Lipid MS Predict Database. Of these, 19 lipid species (from phosphatidylcholine and lysophosphotidylcholine lipid classes) were significantly altered by 6-OHDA, with most being down-regulated. The two lipid species that were up-regulated were LPC (16:0) and LPC (18:1), which are important for neuroinflammatory signalling. These findings provide a first step in the characterization of lipid changes in early stages of PD-like pathology and could provide novel targets for early interventions in PD.

Lipid profiling of parkin‐mutant human skin fibroblasts

“…PD, as other neurodegenerative diseases, is also recognized to have an inflammatory component, yet poorly understood (Qin et al, ). In agreement with these findings, the lipid analysis of the substantia nigra region of an early‐stage rat model of PD has revealed the up‐regulation of the same LPC species, which are considered crucial for neuroinflammatory signaling (Farmer, Smith, Hayley, & Smith, ).…”

Metabolomic biomarkers as strong correlates of Parkinson disease progression

“…33 Another investigation of 6hydroxydopamine-treated rats found that the substantia nigra underwent marked alterations of lipid metabolism, including either downregulation or upregulation for the synthesis of several phosphatidylcholine and lysophosphotidylcholine lipid species. 34 To date, no other biospecimen marker studies have offered correlations as strong as that found for the prediction of change in the clinical measures of PD progression used in this study, which, in our participants, increased by z47% over a mean of 11 months. Our untargeted approach resulted in the discovery of some biomarkers not previously recognized as involved in PD neurodegeneration.…”

Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export

“…ATP10B dysfunction also diminishes lysosomal PC export, which may further contribute to the disease mechanism. Indeed, the PC lipid composition was shown to be disturbed in the substantia nigra of a PD rat model treated with 6-hydroxydopamine [36]. Moreover, loss of function mutations in PLA2G6, encoding a phospholipase involved in repair of oxidative damage to membrane phospholipids, membrane remodeling and iron homeostasis, are also shown to affect neuronal lipid homeostasis [14,83,98].…”