Elevated GM3 plasma concentration in idiopathic Parkinson's disease: A lipidomic analysis

Robin B. Chan, Adler J. Perotte, Bowen Zhou, Christopher Liong, Evan J. Shorr, Karen S. Marder, Un Jung Kang, Cheryl H. Waters, Oren A. Levy, Yimeng Xu, Hong Bin Shim, Itsik Pe'Er, Gilbert Di Paolo, Roy N. Alcalay

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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.

Original languageEnglish
Article numbere0172348
JournalPLoS ONE
Volume12
Issue number2
DOIs
StatePublished - Feb 2017

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Parkinson disease
Parkinson Disease
Plasmas
Lipids
lipids
Glucosylceramidase
Glucosylceramides
ROC Curve
Area Under Curve
Synucleins
Logistic Models
G(M3) Ganglioside
glycosphingolipids
Neurodegenerative diseases
Glycerophospholipids
Lewy Bodies
gangliosides
Glycosphingolipids
sphingolipids
Sphingolipids

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Chan, R. B., Perotte, A. J., Zhou, B., Liong, C., Shorr, E. J., Marder, K. S., ... Alcalay, R. N. (2017). Elevated GM3 plasma concentration in idiopathic Parkinson's disease: A lipidomic analysis. PLoS ONE, 12(2), [e0172348]. https://doi.org/10.1371/journal.pone.0172348
Chan, Robin B. ; Perotte, Adler J. ; Zhou, Bowen ; Liong, Christopher ; Shorr, Evan J. ; Marder, Karen S. ; Kang, Un Jung ; Waters, Cheryl H. ; Levy, Oren A. ; Xu, Yimeng ; Shim, Hong Bin ; Pe'Er, Itsik ; Di Paolo, Gilbert ; Alcalay, Roy N. / Elevated GM3 plasma concentration in idiopathic Parkinson's disease : A lipidomic analysis. In: PLoS ONE. 2017 ; Vol. 12, No. 2.
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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.",
author = "Chan, {Robin B.} and Perotte, {Adler J.} and Bowen Zhou and Christopher Liong and Shorr, {Evan J.} and Marder, {Karen S.} and Kang, {Un Jung} and Waters, {Cheryl H.} and Levy, {Oren A.} and Yimeng Xu and Shim, {Hong Bin} and Itsik Pe'Er and {Di Paolo}, Gilbert and Alcalay, {Roy N.}",
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Chan, RB, Perotte, AJ, Zhou, B, Liong, C, Shorr, EJ, Marder, KS, Kang, UJ, Waters, CH, Levy, OA, Xu, Y, Shim, HB, Pe'Er, I, Di Paolo, G & Alcalay, RN 2017, 'Elevated GM3 plasma concentration in idiopathic Parkinson's disease: A lipidomic analysis', PLoS ONE, vol. 12, no. 2, e0172348. https://doi.org/10.1371/journal.pone.0172348

Elevated GM3 plasma concentration in idiopathic Parkinson's disease : A lipidomic analysis. / Chan, Robin B.; Perotte, Adler J.; Zhou, Bowen; Liong, Christopher; Shorr, Evan J.; Marder, Karen S.; Kang, Un Jung; Waters, Cheryl H.; Levy, Oren A.; Xu, Yimeng; Shim, Hong Bin; Pe'Er, Itsik; Di Paolo, Gilbert; Alcalay, Roy N.

In: PLoS ONE, Vol. 12, No. 2, e0172348, 02.2017.

Research output: Contribution to journalArticle

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T1 - Elevated GM3 plasma concentration in idiopathic Parkinson's disease

T2 - A lipidomic analysis

AU - Chan, Robin B.

AU - Perotte, Adler J.

AU - Zhou, Bowen

AU - Liong, Christopher

AU - Shorr, Evan J.

AU - Marder, Karen S.

AU - Kang, Un Jung

AU - Waters, Cheryl H.

AU - Levy, Oren A.

AU - Xu, Yimeng

AU - Shim, Hong Bin

AU - Pe'Er, Itsik

AU - Di Paolo, Gilbert

AU - Alcalay, Roy N.

PY - 2017/2

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N2 - 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.

AB - 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.

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Chan RB, Perotte AJ, Zhou B, Liong C, Shorr EJ, Marder KS et al. Elevated GM3 plasma concentration in idiopathic Parkinson's disease: A lipidomic analysis. PLoS ONE. 2017 Feb;12(2). e0172348. https://doi.org/10.1371/journal.pone.0172348