Abstract
Parkinson’s disease (PD) is a common neurodegenerative disease whose pathological hallmark is the accumulation of intracellular α-synuclein aggregates in Lewy bodies. Lipid metabolism dysregulation may play a significant role in PD pathogenesis; however, large plasma lipidomic studies in PD are lacking. In the current study, we analyzed the lipidomic profile of plasma obtained from 150 idiopathic PD patients and 100 controls, taken from the ‘Spot’ study at Columbia University Medical Center in New York. Our mass spectrometry based analytical panel consisted of 520 lipid species from 39 lipid subclasses including all major classes of glycerophospholipids, sphingolipids, glycerolipids and sterols. Each lipid species was analyzed using a logistic regression model. The plasma concentrations of two lipid subclasses, triglycerides and monosialodihexosylganglioside (GM3), were different between PD and control participants. GM3 ganglioside concentration had the most significant difference between PD and controls (1.531±0.037 pmol/μl versus 1.337±0.040 pmol/μl respectively; p-value = 5.96E-04; q-value = 0.048; when normalized to total lipid: p-value = 2.890E-05; q-value = 2.933E-03). Next, we used a collection of 20 GM3 and glucosylceramide (GlcCer) species concentrations normalized to total lipid to perform a ROC curve analysis, and found that these lipids compare favorably with biomarkers reported in previous studies (AUC = 0.742 for males, AUC = 0.644 for females). Our results suggest that higher plasma GM3 levels are associated with PD. GM3 lies in the same glycosphingolipid metabolic pathway as GlcCer, a substrate of the enzyme glucocerebrosidase, which has been associated with PD. These findings are consistent with previous reports implicating lower glucocerebrosidase activity with PD risk.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disease, the burden of which is expected to grow as the current population ages
There was no significant difference in gender, age or statin use between PD and control participants
We found that TG levels were about 25% lower in PD patients compared to controls (p-value = 0.0041; q-value = 0.0497; when normalized to total lipid: p-value 5.837E-03; q-value = 2.382E-02; S2 Table); because of a greater variance, statistical significance of the differences in TG plasma levels was not as strong as differences in GM3 levels
Summary
Parkinson’s disease (PD) is a common neurodegenerative disease, the burden of which is expected to grow as the current population ages. Biophysical evidence suggests that α-synuclein binds preferentially to acidic phospholipids over lipids with net neutral charge. Such interactions could potentially play a role in modulating the catalytic activity of various cytoplasmic lipid enzymes as well as lysosomal lipases that are dependent on negatively charged lipids [7,8]. Further support of the importance of lipid dysregulation in PD is driven by genetic studies, where mutations in glucocerebrosidase (GBA) are strongly associated with PD [9]. GBA encodes the lysosomal enzyme β-glucosidase (GCase), which hydrolyzes glucosylceramide and glucosylsphingosine to ceramide and sphingosine, respectively, and plays a key role in the glycosphingolipid metabolic pathway. A recent study showed an association between apolipoprotein A1 (ApoA1) and several clinical variables in PD, including earlier age-at-onset [17]
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