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. 2022 Dec 16;17(12):e0279315.
doi: 10.1371/journal.pone.0279315. eCollection 2022.

Plasma sphingolipid abnormalities in neurodegenerative diseases

Hideki Oizumi  1 , Yoko Sugimura  1 , Tomoko Totsune  1 , Iori Kawasaki  1 , Saki Ohshiro  1 , Toru Baba  1 , Teiko Kimpara  1 , Hiroaki Sakuma  1 , Takafumi Hasegawa  2 , Ichiro Kawahata  3 , Kohji Fukunaga  3 , Atsushi Takeda  1   4
Affiliations

Plasma sphingolipid abnormalities in neurodegenerative diseases

Hideki Oizumi et al. PLoS One. .

Abstract

Background: In recent years, there has been increasing evidence that several lipid metabolism abnormalities play an important role in the pathogenesis of neurodegenerative diseases. However, it is still unclear which lipid metabolism abnormalities play the most important role in neurodegenerative diseases. Plasma lipid metabolomics (lipidomics) has been shown to be an unbiased method that can be used to explore lipid metabolism abnormalities in neurodegenerative diseases. Plasma lipidomics in neurodegenerative diseases has been performed only in idiopathic Parkinson's disease (IPD) and Alzheimer's disease (AD), and comprehensive studies are needed to clarify the pathogenesis.

Methods: In this study, we investigated plasma lipids using lipidomics in individuals with neurodegenerative diseases and healthy controls (CNs). Plasma lipidomics was evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in those with IPD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), AD, and progressive supranuclear palsy (PSP) and CNs.

Results: The results showed that (1) plasma sphingosine-1-phosphate (S1P) was significantly lower in all neurodegenerative disease groups (IPD, DLB, MSA, AD, and PSP) than in the CN group. (2) Plasma monohexylceramide (MonCer) and lactosylceramide (LacCer) were significantly higher in all neurodegenerative disease groups (IPD, DLB, MSA, AD, and PSP) than in the CN group. (3) Plasma MonCer levels were significantly positively correlated with plasma LacCer levels in all enrolled groups.

Conclusion: S1P, Glucosylceramide (GlcCer), the main component of MonCer, and LacCer are sphingolipids that are biosynthesized from ceramide. Recent studies have suggested that elevated GlcCer and decreased S1P levels in neurons are related to neuronal cell death and that elevated LacCer levels induce neurodegeneration by neuroinflammation. In the present study, we found decreased plasma S1P levels and elevated plasma MonCer and LacCer levels in those with neurodegenerative diseases, which is a new finding indicating the importance of abnormal sphingolipid metabolism in neurodegeneration.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Fig 1
Fig 1. Plasma S1P levels in neurodegenerative diseases.
(A) Plasma S1P d16.1 levels were significantly lower in the IPD group of cohort A (p < 0.0001) than in the CN group. (B) Plasma S1P d16.1 levels were significantly lower in the DLB group (p < 0.0001) and AD group (p < 0.0001) than in the CN group. (C) Plasma S1P d16.1 levels were significantly lower in the IPD group of cohort C (p < 0.01), MSA group (p < 0.01) and PSP group (p < 0.001) than in the CN group. (D) Plasma S1P d18.1 levels were significantly lower in the IPD group of cohort A (p < 0.05) than in the CN group. (E) Plasma S1P d18.1 levels were significantly lower in the DLB group (p < 0.01) and AD group (p < 0.05) than in the CN group. (F) Plasma S1P d18.1 levels were significantly lower in the IPD group of cohort C (p < 0.05), MSA group (p < 0.05) and PSP group (p < 0.05) than in the CN group. Statistical significance was examined using one-tailed Welch’s t tests (P < 0.05). Circles indicate the data points between the lower and upper whiskers, and x indicates the average marker in a box/whisker diagram.
Fig 2
Fig 2. Plasma MonCer levels in neurodegenerative diseases.
(A) Plasma MonCer d18:1 levels were significantly higher in the IPD group of cohort A (p < 0.01) than in the CN group. (B) Plasma MonCer d18:1 levels were significantly higher in the DLB group (p < 0.01) and AD group (p < 0.001) than in the CN group. (C) Plasma MonCer d18:1 levels were significantly higher in the IPD group of cohort C (p < 0.01), MSA group (p < 0.05) and PSP group (p < 0.01) than in the CN group. Statistical significance was examined using one-tailed Welch’s t tests (P < 0.05). Circles indicate the data points between the lower and upper whiskers, and x indicates the average marker in a box/whisker diagram.
Fig 3
Fig 3. Plasma LacCer levels in neurodegenerative diseases.
(A) Plasma LacCer d18:1 levels were significantly higher in the IPD group of cohort A (p < 0.01) than in the CN group. (B) Plasma LacCer d18:1 levels were significantly higher in the DLB group (p < 0.001) and AD group (p < 0.05) than in the CN group. (C) Plasma LacCer d18:1 levels were significantly higher in the IPD group of cohort C (p < 0.01), MSA group (p < 0.01) and PSP group (p < 0.01) than in the CN group. Statistical significance was examined using one-tailed Welch’s t tests (P < 0.05). Circles indicate the data points between the lower and upper whiskers, and x indicates the average marker in a box/whisker diagram.
Fig 4
Fig 4. Correlation between total plasma MonCer levels and total plasma LacCer levels.
(A) Total plasma MonCer d18:1 levels were significantly positively correlated with total plasma LacCer d18:1 levels (r = 0.5802, p < 0.0001) in all enrolled groups.
Fig 5
Fig 5. Ceramide, sphingosine and glycosphingolipid metabolism.
Products are indicated in bold and italics. Abbreviations: S1P, sphingosine-1-phosphate; GlcCer, glucosylceramide; GCase, glucocerebrosidase; GCS, GlcCer synthase; CERase, ceramidase; CERS, ceramide synthase; SPHK, sphingosine kinase; SGPP, S1P phosphatase; BGTase6, beta-1,4-galactosyltransferase 6; BGase, beta-galactosidase.
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