Elevation of gangliosides in four brain regions from Parkinson’s disease patients with a GBA mutation

Blumenreich, Shani; Nehushtan, Tamar; Barav, Or B.; Saville, Jennifer T.; Dingjan, Tamir; Hardy, John; Fuller, Maria; Futerman, Anthony H.

doi:10.1038/s41531-022-00363-2

Cited by 14 publications

(25 citation statements)

References 47 publications

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“…In patients with PD, GCase deficiency specific to the SN was reported, 34 but in either putamen or cerebellum of patients with PD with or without GBA mutation(s), there were no or few changes in glucosylsphingosine, sphingomyelin, gangliosides (GM2, GM3), or total cholesterol. 8,39,40 In fact, other studies even reported reduced glycosphingolipids in brain regions with significant PD pathology (discussed in Lansbury 17 ) and compensatory upregulation of ceramide synthase-1 gene expression, 30 which would possibly increase overall sphingolipid recycling per time (flux). In PD, multiple glycosphingolipid abnormalities were observed in plasma independent of changes in GlcCer or GCase.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…The PD patients were classi ed as IPD and most displayed characteristic Lewy body (LB) pathology, according to the case study data. For PD-GBA brains 13 , GBA1 mutations included, among others, patients with the N370S and the L444P mutations which are found at high levels in association with PD 3 . The same samples were used for a recent non-targeted lipidomics study, in which elevation of levels of gangliosides was detected in four brain regions 13 , although no signi cant changes were observed in levels of GlcCer.…”

Section: Methodsmentioning

confidence: 99%

“…A number of approaches have been used to attempt to delineate the mechanistic relationship between PD and GBA1 mutations, among them, high throughput omics [9][10][11][12] . Recently we used a unique tissue collection of brain tissues from idiopathic PD (IPD) and PD-GBA patients to perform a non-targeted lipidomics analysis of four different brain regions 13 , namely the striatum (STR), which is part of the nigrostriatal dopaminergic pathway, and also the occipital cortex (OCC), middle temporal gyrus (MTG) and cingulate gyrus (CG). No changes in levels of glucosylceramide (GlcCer), the substrate of GCase, were observed although levels of gangliosides (sialic acid-containing glycosphingolipids) were elevated in 3 of the 4 brain regions in such a way that suggests upregulation of the pathway of ganglioside metabolism rather than modulation of the activity of speci c enzymes in the pathway.…”

Section: Introductionmentioning

confidence: 99%

“…In the current study, we use the same tissue collection 13 but with the inclusion of the substantia nigra (SN), and perform non-targeted, mass spectrometry based quantitative discovery proteomics of all ve brain areas. Although a number of studies of human PD brain have been performed (reviewed in 14,15 ), very few used more than one brain region from the same patients to allow comparison of possible changes across the same brain.…”

Section: Introductionmentioning

confidence: 99%

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Large-scale proteomics analysis of five brain regions from Parkinson’s disease patients with a GBA1 mutation

Blumenreich

Nehushtan

Kupervaser

et al. 2023

Preprint

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Despite being the second most common neurodegenerative disorder, little is known about Parkinson’s disease (PD) pathogenesis. A number of genetic factors predispose towards PD, among them mutations in GBA1, which encodes the lysosomal enzyme acid-β-glucosidase. We now perform non-targeted, mass spectrometry based quantitative proteomics on five brain regions from PD patients with a GBA1 mutation (PD-GBA) and compare to age- and sex-matched idiopathic PD patients and controls. Two proteins were differentially-expressed in all five brain regions whereas significant differences were detected between the brain regions, with changes consistent with loss of dopaminergic signaling in the substantia nigra, and activation of a number of pathways in the cingulate gyrus, including ceramide synthesis. Mitochondrial oxidative phosphorylation was inactivated to a larger extent in IPD samples in most brain regions compared to controls and to a larger extent in PD-GBA. This is the first large-scale proteomics dataset generated for the study of PD-GBA.

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“…1). However, these GCase activity and lipid changes have only been observed in certain regions, at certain ages, and have not been found consistently across cohorts [24][25][26][27] . Most previous studies have focused on either GCase activity or glycosphingolipid analyses; idiopathic or GBA1 PD, making it difficult to draw conclusions across studies.…”

Section: Introductionmentioning

confidence: 92%

Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease

Leyns

Prigent

Beezhold

et al. 2022

Preprint

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Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases characterized by the accumulation of misfolded α-synuclein in the form of Lewy pathology. While most cases are sporadic, there are rare genetic mutations that cause disease and more common variants that increase incidence of disease. The most prominent genetic mutations for PD and DLB are in the GBA1 and LRRK2 genes. GBA1 mutations are associated with decreased glucocerebrosidase activity and lysosomal accumulation of its lipid substrates, glucosylceramide and glucosylsphingosine. Previous studies have shown a link between this enzyme and lipids even in sporadic PD. However, it is unclear how the protein pathologies of disease are related to enzyme activity and glycosphingolipid levels. To address this gap in knowledge, we examined quantitative protein pathology, glucocerebrosidase activity and lipid substrates in parallel from 4 regions of 91 brains with no neurological disease, idiopathic, GBA1-linked, or LRRK2-linked PD and DLB. We find that several biomarkers are altered with respect to mutation and disease severity. We found mild association of glucocerebrosidase activity with disease, but a strong association of glucosylsphingosine with 8α-synuclein pathology, irrespective of genetic mutation. This association suggests that Lewy pathology precipitates changes in lipid levels related to disease severity.

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Elevation of gangliosides in four brain regions from Parkinson’s disease patients with a GBA mutation

Cited by 14 publications

References 47 publications

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

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

Large-scale proteomics analysis of five brain regions from Parkinson’s disease patients with a GBA1 mutation

Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease

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