Glycosphingolipid Changes in Plasma in Parkinson's Disease Independent of Glucosylceramide Levels

Vruchte, Daniëlle te; Sturchio, Andrea; Priestman, David A.; Tsitsi, Panagiota; Hertz, Ellen; Andréasson, Mattias; Markaki, Ioanna; Wallom, Kerri‐Lee; Platt, Frances M.; Svenningsson, Per

doi:10.1002/mds.29163

Cited by 8 publications

(28 citation statements)

References 30 publications

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“…This correlation breaks down if the sum of all GM3 isomers is compared, highlighting the importance of measuring each individual isomer. The te Vrucht et al 1 article also reports correlations between plasma Gb4 and UPDRS3 (especially in males) and between GD1b and MoCA. These findings need to be confirmed in larger populations.…”

Section: Do Plasma Sphingolipid Levels Correlate With Pd Symptoms?mentioning

confidence: 91%

“…the dynamics, rather than the static SL levels, that is driving disease progression. 1 Static levels of several other headgroup-defined classes of SL are changed in iPD and GBA-PD relative to healthy control subjects, but all of these are comparable in iPD and GBA-PD. Therefore, determination of whether these changes are an effect or a driver of disease is not possible.…”

Section: Sphingolipids Are Most Precisely Identified and Measured By ...mentioning

confidence: 93%

“…Two studies, including te Vrucht et al, 1 have observed correlations between plasma SL levels and PD symptoms. One study observed that the elevation of several side‐chain isomers of GM3 is correlated with PD severity 16 .…”

Section: Do Plasma Sphingolipid Levels Correlate With Pd Symptoms?mentioning

confidence: 98%

“…Importantly, this difference does not result from the GCase deficit, because the patients with GBA‐PD and iPD are indistinguishable 1 . In fact, no static differences in any SL head group were observed between GBA‐PD and iPD, one more piece of evidence that it is the dynamics, rather than the static SL levels, that is driving disease progression 1 . Static levels of several other headgroup‐defined classes of SL are changed in iPD and GBA‐PD relative to healthy control subjects, but all of these are comparable in iPD and GBA‐PD.…”

Section: Sphingolipids Are Most Precisely Identified and Measured By ...mentioning

confidence: 99%

“…Such a change could have important physiological consequences, because the two acyl chains confer different membrane properties. Despite these limitations, te Vrucht et al's data 1 represent a significant addition to the collective knowledge, in part because it illustrates the complexities of sphingolipid metabolism and raises important questions for future exploration.…”

Section: Sphingolipids Are Most Precisely Identified and Measured By ...mentioning

confidence: 99%

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The Sphingolipids Clearly Play a Role in Parkinson's Disease, but Nature Has Made it Complicated

Lansbury

2022

Movement Disorders

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A recent article in this journal 1 adds to a growing avalanche of data concerning the relationship between sphingolipid metabolism and Parkinson's disease (PD). The focus on this connection owes to the fact that mutations in the GBA1 gene have been linked to the risk and the rate of progression of PD (GBA1 is one of a very few genes that are related to both 2,3 ). GBA1 encodes the lysosomal enzyme glucocerebrosidase (GCase), which catalyzes the hydrolysis of the sphingolipid glucosylceramide (GluCer) to produce ceramide (Fig. 1). Progressionrelated single-allele mutations are associated with a mild (10-50%) loss of GCase activity. Inheritance of two mutant alleles produces a much more severe deficit of GCase activity (typically 90%) and Gaucher's disease. In Gaucher's disease, GluCer accumulates in peripheral cells, as predicted by Michaelis-Menten kinetics. 4 This same analysis stated that GluCer accumulation would not be expected to occur in the case of mild loss of GCase activity (as in GBA-PD). Unfortunately, its conclusion was widely ignored (including by me, for a time), and the hypothesis that GluCer accumulation occurs in GBA-PD and may drive GBA-PD progression took root despite the lack of experimental evidence.

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Section: Do Plasma Sphingolipid Levels Correlate With Pd Symptoms?mentioning

confidence: 91%

Section: Sphingolipids Are Most Precisely Identified and Measured By ...mentioning

confidence: 93%

Section: Do Plasma Sphingolipid Levels Correlate With Pd Symptoms?mentioning

confidence: 98%

Section: Sphingolipids Are Most Precisely Identified and Measured By ...mentioning

confidence: 99%

Section: Sphingolipids Are Most Precisely Identified and Measured By ...mentioning

confidence: 99%

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The Sphingolipids Clearly Play a Role in Parkinson's Disease, but Nature Has Made it Complicated

Lansbury

2022

Movement Disorders

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A Biomarker Study in Patients with GBA1‐Parkinson's Disease and Healthy Controls

et al. 2023

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A BS TRACT: Background: Molecules related to glucocerebrosidase (GCase) are potential biomarkers for development of compounds targeting GBA1-associated Parkinson's disease (GBA-PD). Objectives: Assessing variability of various glycosphingolipids (GSLs) in plasma, peripheral blood mononuclear cells (PBMCs), and cerebrospinal fluid (CSF) across GBA-PD, idiopathic PD (iPD), and healthy volunteers (HVs). Methods: Data from five studies were combined. Variability was assessed of glucosylceramide (various isoforms), lactosylceramide (various isoforms), glucosylsphingosine, galactosylsphingosine, GCase activity (using fluorescent 4-methylumbeliferryl-β-glucoside), and GCase protein (using enzyme-linked immunosorbent assay) in plasma, PBMCs, and CSF if available, in GBA-PD, iPD, and HVs. GSLs in leukocyte subtypes were compared in HVs. Principal component analysis was used to explore global patterns in GSLs, clinical characteristics (Movement Disorder Society -Unified Parkinson's Disease Rating Scale Part 3 [MDS-UPDRS-3], Mini-Mental State Examination [MMSE], GBA1 mutation type), and participant status (GBA-PD, iPD, HVs). Results: Within-subject between-day variability ranged from 5.8% to 44.5% and was generally lower in plasma than in PBMCs. Extracellular glucosylceramide levels (plasma) were slightly higher in GBA-PD compared with both iPD and HVs, while intracellular levels were comparable. GSLs in the different matrices (plasma, PBMCs, CSF) did not correlate. Both lactosylceramide and glucosylsphingosine were more abundant in granulocytes compared with monocytes and lymphocytes. Absolute levels of GSL isoforms differed greatly. GBA1 mutation types could not be differentiated based on GSL data. Conclusions: Glucosylceramide can stably be measured over days in both plasma and PBMCs and may be used as a biomarker in clinical trials targeting GBA-PD. Glucosylsphingosine and lactosylceramide are stable in plasma but are strongly affected by leukocyte subtypes in PBMCs. GBA-PD could be differentiated from iPD and HVs, primarily based on glucosylceramide levels in plasma.

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Double‐Edged Effects of Venglustat on Behavior and Pathology in Mice Overexpressing α‐Synuclein

Schidlitzki¹,

Stanojlović²,

Fournier

et al. 2023

Movement Disorders

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A BS TRACT: Background: Venglustat is a brain-penetrant, small molecule inhibitor of glucosylceramide synthase used in clinical testing for treatment of Parkinson's disease (PD). Despite beneficial effects in certain cellular and rodent models, patients with PD with mutations in GBA, the gene for lysosomal glucocerebrosidase, experienced worsening of their motor function under venglustat treatment (NCT02906020, MOVES-PD, phase 2 trial). Objective: The objective of this study was to evaluate venglustat in mouse models of PD with overexpression of wild-type α-synuclein. Methods: Mice overexpressing α-synuclein (Thy1-aSyn line 61) or Gba-mutated mice with viral vector-induced overexpression of α-synuclein in the substantia nigra were administered venglustat as food admixture. Motor and cognitive performance, α-synuclein-related pathology, and microgliosis were compared with untreated controls. Results: Venglustat worsened motor function in Thy1-aSyn transgenics on the challenging beam and the pole test. Although venglustat did not alter the cognitive deficit in the Y-maze test, it alleviated anxiety-related behavior in the novel object recognition test. Venglustat reduced soluble and membrane-bound α-synuclein in the striatum and phosphorylated α-synuclein in limbic brain regions. Although venglustat reversed the loss of parvalbumin immunoreactivity in the basolateral amygdala, it tended to increase microgliosis and phosphorylated α-synuclein in the substantia nigra. Furthermore, venglustat also partially worsened motor performance and tended to increase neurofilament light chain in the cerebrospinal fluid in the Gbadeficient model with nigral α-synuclein overexpression and neurodegeneration. Conclusions: Venglustat treatment in two mouse models of α-synuclein overexpression showed that glucosylceramide synthase inhibition had differential detrimental or beneficial effects on behavior and neuropathology possibly related to brain region-specific effects.

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Glycosphingolipid Changes in Plasma in Parkinson's Disease Independent of Glucosylceramide Levels

Cited by 8 publications

References 30 publications

The Sphingolipids Clearly Play a Role in Parkinson's Disease, but Nature Has Made it Complicated

The Sphingolipids Clearly Play a Role in Parkinson's Disease, but Nature Has Made it Complicated

A Biomarker Study in Patients with GBA1‐Parkinson's Disease and Healthy Controls

Double‐Edged Effects of Venglustat on Behavior and Pathology in Mice Overexpressing α‐Synuclein

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