Glycosphingolipid Levels Altered in Blood of Parkinson’s Patients: Study

Some alterations were linked to motor and cognitive impairments

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Multiple alterations to a class of fat (lipid) molecules called glycosphingolipids (GSLs) are observed in the blood of people with Parkinson’s disease compared with those without the disease, according to a recent study.

These changes, some of which are linked to Parkinson’s symptoms such as motor and cognitive impairments in patients, are independent of whether patients had alterations in glucosylceramide (Glc-Cer), a molecule previously found to influence GSL levels due to genetic mutations in patients.

The findings support the notion that there are broad alterations to lipid signaling in Parkinson’s that may underlie some disease processes, according to researchers.

The study, “Glycosphingolipid Changes in Plasma in Parkinson’s Disease Independent of Glucosylceramide Levels,” was published in Movement Disorders

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What’s the role of glycosphingolipids in Parkinson’s?

Recent evidence has suggested that changes in some lipids, particularly GSLs, may be involved in the development of Parkinson’s. These fatty molecules play a range of roles in cell growth, development, and signaling.

In particular, mutations in GBA1, a gene encoding the glucocerebrosidase (GCase) enzyme, were found to be the most common genetic risk factor for Parkinson’s. GCase normally acts to degrade Glc-Cer, a precursor molecule to GSLs.

It’s been proposed that these GBA1 mutations may lower GCase activity, leading to the accumulation of Glc-Cer and increased GSL synthesis that disrupts cellular function.

But the potential role of GSLs in Parkinson’s still requires more investigation, researchers say.

To learn more, a team of researchers analyzed the blood levels of Glc-Cer and various GSLs in a group of Parkinson’s patients in Sweden compared with people who did not have the disease and served as controls.

Blood samples were analyzed from 8o patients, with a median age of 64, and 25 healthy controls with a median age of 66. Significantly more controls (72%) were women compared with the Parkinson’s group, in which 33.8% were women.

Participants were screened for known GBA1 mutations. Overall, 15 people with Parkinson’s and five in the control group had a mutation. Most of these mutations were considered “low-risk,” according to the researchers.

What did the researchers discover?

GlcCer levels and a number of GSLs were found to be significantly increased in Parkinson’s patients compared with controls. In contrast, a handful of individual molecules and total GSL levels were lower in patients than in controls.

No GSL differences were observed between mutation carriers and non-carriers.

To learn more about whether elevations in GlcCer were specifically associated with GSL changes, the patients were stratified based on whether  they had “normal” or “high” levels of GlcCer. High GlcCer was considered to be levels above 8.38 nanomoles per milliliter (nm/mL), a value over two standard deviations above the mean level in healthy people.

Among the patients, 50 had high GlcCer, and 11 of them were carriers of a GBA1 mutation. Total GSLs, and some individual molecules, including GM1a, GM3, a-series and b-series, were different between the controls and Parkinson’s patients with normal GlcCer, but not patients with high GlcCer.

GD1b, GT1b, GM2, and Gb4 were different between patients and the controls regardless of GlcCer level.

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Some clinical characteristics of Parkinson’s were associated with GSL levels. Specifically, higher Gb4 levels correlated with worse motor symptoms, as measured by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale part III.

In contrast, higher GDb1 and GD1-alpha were each associated with better cognitive function, as measured by the Montreal Cognitive Assessment. When mutation carriers were removed from the analysis, GD1-alpha was no longer linked to cognitive performance.

When patients were stratified by sex, only male GSL levels were linked to these clinical features, a finding that could be due to the greater proportion of male patients in the analysis, the team noted.

Overall, “this study shows that abnormalities in these [GSL] pathways can be present independently of the accumulation of GlcCer due to genetic mutation or normal aging,” the researchers wrote.

When patients do have diminished GCase activity, it could instead act as a “’second hit’ in a landscape of already-altered GSLs metabolism,” the researchers added.

The team noted that while GSL alterations appear evident in Parkinson’s patients, the finding “does not allow the evaluation of the causality of our associations, and replicating these results in another cohort would be important to validate these findings.”

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