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

Lansbury, Peter T.

doi:10.1002/mds.29204

Cited by 11 publications

(18 citation statements)

References 22 publications

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“…Over the last several years, there has been an increasing appreciation for the role that gangliosides and sphingolipids in general may play in the pathogenesis and progression of neurodegenerative diseases ( Maglione et al, 2010 ; Di Pardo and Maglione, 2018 ; Lansbury, 2022 ) and PD in particular ( Chiricozzi et al, 2020 ; Ledeen et al, 2022 ; Schneider, 2022 ). However, less attention has been paid to the roles that possible alterations in expression of genes involved in glycosylation, sialylation, and S1P regulation may play in the development and progression of PD.…”

Section: Discussionmentioning

confidence: 99%

Altered expression of glycobiology-related genes in Parkinson’s disease brain

Schneider

Singh

2022

Front. Mol. Neurosci.

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The precise mechanisms initiating and perpetuating the cellular degeneration in Parkinson’s disease (PD) remain unclear. There is decreased expression of the main brain gangliosides, and GM1 ganglioside in particular, in the PD brain along with decreased expression of the genes coding for the glycosyltranferase and the sialyltransferase responsible for the synthesis of these brain gangliosides. However, potentially important pathogenic mechanisms contributing to the neurodegeneration in PD may also include altered levels of expression of genes involved in glycosylation, sialylation and sphingolipid synthesis and metabolism. Although various studies have described pathological lipid and glycolipid changes in PD brain, there have been limited studies of expression of glycobiology-related genes in PD brain. The current study was performed as an initial attempt to gain new information regarding potential changes in glycoprotein and glycolipid-related genes in PD by investigating the gene expression status for select glycosyltransferases, sialyltransferases, sialidases, sphingosine kinases, and lysosomal enzymes in the substantia nigra and putamen from patients with PD and neurologically normal controls. Results showed altered expression of glycosyltransferase genes (B3GALT2 and B4GALT1) potentially involved in microglial activation and neuroinflammation, sphingosine-1-phosphate (S1P) modulators (SPHK1, SPHK2, and SGPL1) involved in sphingolipid synthesis and metabolism, polysialyltransferase genes (ST8SIA2 and ST8SIA4) that encode enzymes responsible for polysialic acid (polySia) biosynthesis, and the sialidase NEU4, expression of which has been linked to the clearance of storage materials from lysosomes. The data presented here underscore the complexity of the glycolipid/sphingolipid dysregulation in the PD brain and continued and expanded study of these processes may not only provide a greater understanding of the complex roles of aberrant glycosylation sialylation, and sphingolipid synthesis/metabolism in the pathophysiology of PD but may identify potential druggable targets for PD therapeutics.

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Section: Discussionmentioning

confidence: 99%

Altered expression of glycobiology-related genes in Parkinson’s disease brain

Schneider

Singh

2022

Front. Mol. Neurosci.

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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%

“…41 Thus, GlcCer in brain or plasma appears not to be the most appropriate reporter for shifts in lipid homeostasis. 17 Considering these aspects and the fact that the loss of one GBA allele in GBA-PD is not expected to result in significant GlcCer accumulation, it has been questioned whether GCS inhibition is in fact a valid approach to treat PD. 17 To add to this complexity, our data support the general notion in the field that sphingolipid composition may differ between brain regions and throughout disease progression and, therefore, that global GCS inhibition may possibly be benign for some neuronal circuits affected by disease, but not for others.…”

Section: Discussionmentioning

confidence: 99%

“…12 Venglustat was tested in healthy volunteers in a phase 1 trial 15 and recently in a phase 2 trial in patients with PD heterozygous for GBA mutations (NCT02906020, MOVES-PD). Venglustat was reported in 2021 to have worsened motor function in patients (Movement Disorder Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS]), 16,17 despite successful reduction of GlcCer levels in cerebrospinal fluid (CSF), indicating target engagement. 16 Back to bench research is required to investigate the potential mechanisms involved and to improve predictive validity of preclinical studies.…”

Section: Introductionmentioning

confidence: 99%

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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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“…However, in one GBA -PD cohort mild increases in levels of Cer, hexosylceramide (GlcCer and GalCer) and LacCer were observed in serum samples ( Guedes et al, 2017 ). The lack of compelling evidence may be due to the nature of the samples that were studied or the dynamic flux in SLs ( Lansbury, 2022 ). However, a role for SLs in the progression of PD is supported by studies in animal models, mostly in fruit flies.…”

Section: Parkinson’s Disease and Parkinsonismmentioning

confidence: 99%

Sphingolipids in neurodegenerative diseases

Pan

Dutta

et al. 2023

Front. Neurosci.

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Neurodegenerative Diseases (NDDs) are a group of disorders that cause progressive deficits of neuronal function. Recent evidence argues that sphingolipid metabolism is affected in a surprisingly broad set of NDDs. These include some lysosomal storage diseases (LSDs), hereditary sensory and autonomous neuropathy (HSAN), hereditary spastic paraplegia (HSP), infantile neuroaxonal dystrophy (INAD), Friedreich’s ataxia (FRDA), as well as some forms of amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). Many of these diseases have been modeled in Drosophila melanogaster and are associated with elevated levels of ceramides. Similar changes have also been reported in vertebrate cells and mouse models. Here, we summarize studies using fly models and/or patient samples which demonstrate the nature of the defects in sphingolipid metabolism, the organelles that are implicated, the cell types that are initially affected, and potential therapeutics for these diseases.

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

Cited by 11 publications

References 22 publications

Altered expression of glycobiology-related genes in Parkinson’s disease brain

Altered expression of glycobiology-related genes in Parkinson’s disease brain

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

Sphingolipids in neurodegenerative diseases

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