GBA mutations, glucosylceramide and Parkinson's disease

Milenković, Ivan; Blumenreich, Shani; Futerman, Anthony H.

doi:10.1016/j.conb.2021.11.004

Cited by 32 publications

(32 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A number of studies have investigated whether the mechanistic link between GBA and PD is related to altered levels of either GlcCer or GlcSph in the brain (reviewed in ref. 9 ). Many of these studies measured lipid levels in the substantia nigra, where loss of dopaminergic neurons occurs, and as a consequence interpretation of changes in GlcCer and GlcSph levels might be confounded by loss of cellular material due to loss of neurons rather than due to specific alterations in levels of a particular lipid class or species.…”

Section: Introductionmentioning

confidence: 99%

“…Many of these studies measured lipid levels in the substantia nigra, where loss of dopaminergic neurons occurs, and as a consequence interpretation of changes in GlcCer and GlcSph levels might be confounded by loss of cellular material due to loss of neurons rather than due to specific alterations in levels of a particular lipid class or species. To date, there is little evidence that GlcCer or GlcSph accumulate in brain samples from human PD or PD-GBA patients 9 , 10 , although some Lewy body disease patients with a GBA mutation show small but non-significant changes in GlcCer levels 11 . There is no evidence for GlcCer accumulation in the brains of heterozygous individuals with a GBA mutation, although there is a suggestion that GlcSph, but not GlcCer levels are elevated in the plasma of GBA carriers 12 , while a different analysis reported normal plasma GlcSph levels in GBA carriers 13 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Blumenreich

Nehushtan

Barav

et al. 2022

npj Parkinsons Dis.

Self Cite

View full text Add to dashboard Cite

A number of genetic risk factors have been identified over the past decade for Parkinson’s Disease (PD), with variants in GBA prominent among them. GBA encodes the lysosomal enzyme that degrades the glycosphingolipid, glucosylceramide (GlcCer), with the activity of this enzyme defective in Gaucher disease. Based on the ill-defined relationship between glycosphingolipid metabolism and PD, we now analyze levels of various lipids by liquid chromatography/electrospray ionization-tandem mass spectrometry in four brain regions from age- and sex-matched patient samples, including idiopathic PD, PD patients with a GBA mutation and compare both to control brains (n = 21 for each group) obtained from individuals who died from a cause unrelated to PD. Of all the glycerolipids, sterols, and (glyco)sphingolipids (251 lipids in total), the only lipid class which showed significant differences were the gangliosides (sialic acid-containing complex glycosphingolipids), which were elevated in 3 of the 4 PD-GBA brain regions. There was no clear correlation between levels of individual gangliosides and the genetic variant in Gaucher disease [9 samples of severe (neuronopathic), 4 samples of mild (non-neuronopathic) GBA variants, and 8 samples with low pathogenicity variants which have a higher risk for development of PD]. Most brain regions, i.e. occipital cortex, cingulate gyrus, and striatum, did not show a statistically significant elevation of GlcCer in PD-GBA. Only one region, the middle temporal gyrus, showed a small, but significant elevation in GlcCer concentration in PD-GBA. We conclude that changes in ganglioside, but not in GlcCer levels, may contribute to the association between PD and GBA mutations.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Blumenreich

Nehushtan

Barav

et al. 2022

npj Parkinsons Dis.

Self Cite

View full text Add to dashboard Cite

show abstract

“…LMNA (lamin A/C) [187], PFKFB3 [188], TRAF2 [189], ADORA2B [190], ACADS (acyl-CoA dehydrogenase short chain) [191], IRF7 [192], ASL (argininosuccinatelyase) [193], IL15 [194], PIK3R1 [195], OSM (oncostatin M) [196], SOCS3 [197], CHD9 [198], IFI44L [199], GNLY (granulysin) [200], FLNB (filamin B) [201], IL1R1 [202], SETD3 [203], TP53 [204], BRD4 [205], COX2 [206], HSP90AB1 [207], SLC7A1 [208], ND2 [209] and COX1 [210] have been reported to be associated with hypertension. LMNA (lamin A/C) [211], INPP5K [212], SCYL1 [213], AKR7A2 [214], TRAF2 [215], SLC11A2 [216], NEU1 [217], SNAP29 [218], DUSP22 [219], P2RX4 [220], ADORA2B [221], NAXD (NAD(P)HX dehydratase) [222], FEZ1 [223], TBK1 [224], GRN (granulin precursor) [225], ATG4D [226], CTSD (cathepsin D) [227], PPP2R5D [228], IRF7 [229], ACAA1 [230], S1PR1 [231], PGRMC1 [169], MAPK14 [232], IL15 [233], OSM (oncostatin M) [234], GBA (glucosylceramidase beta) [235], SOCS3 [236], GLUL (glutamate-ammonia ligase) [175], MON1A [237], LMAN2L [238], RHOC (ras homolog family member C) [239], TUBB2A [240], CHP1 [241], TP53 [242], ATXN1 [243], JARID2 [244], IFNG (interferon gamma) [245], NUCKS1 [246], CTBP1 [247], DNAJC3 [180], ATP6 [248], BRD4 [249], EIF4B [250], COX2 [251], SFPQ (splicing factor proline and glutamine rich) [252], PCBP1 [253], RPL5 [254], HSP90AB1 [255], TRA2A […”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis of next generation sequencing data for Risk Prediction in Patients with Type 1 diabetes mellitus

Vastrad¹,

Vastrad²

2022

Preprint

View full text Add to dashboard Cite

Type 1 diabetes mellitus (T1DM) comprise the most common forms of autoimmune disease. The aim of this investigation was to apply a bioinformatics approach to reveal related pathways or genes involved in the development of T1DM. The next generation sequencing (NGS) dataset GSE182870 was downloaded from the gene expression omnibus (GEO) database. Differentially expressed gene (DEG) analysis was performed using DESeq2. The g:Profiler was utilized to analyze the functional enrichment, gene ontology (GO) and REACTOME pathway of the differentially expressed genes. Protein-protein interaction (PPI) network, modules, miRNA-hub gene regulatory network, and TF-hub gene regulatory network were conducted via comprehensive target prediction and network analyses. Finally, hub genes were validated by using receiver operating characteristic curve analysis. A total of 860 DEGs were screened out from NGS dataset, among which 477 genes were up regulated and 383 genes were down regulated. GO enrichment analysis indicated that up regulated genes were mainly involved in cellular metabolic process, intracellular anatomical structure and catalytic activity, and the down regulated genes were significantly enriched in cellular nitrogen compound biosynthetic process, protein containing complex and heterocyclic compound binding. REACTOME pathway enrichment analysis showed that the up regulated genes were mainly enriched in metabolism of carbohydrates and the down regulated genes were significantly enriched in metabolism of RNA. A PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network were constructed, and hub genes (MAPK14, RHOC, MAD2L1, TAF1, TRAF2, HSP90AA1, TP53, HSP90AB1, UBA52 and RACK1) were identified. This study provides further insights into the underlying pathogenesis of T1DM.

show abstract

“…Decreased glucocerebrosidase levels favor α-synuclein deposits [ 121 ]. Glucosylceramide accumulation in neurons has been demonstrated to cause neuroinflammation and neurodegeneration that ultimately lead to neuron death [ 122 ], but, strangely, even if glucocerebrosidase activity is reduced in PD, there is little evidence of an increase of glucosylceramide [ 123 ]. However, glucosylceramide along with Cer was found to be increased in cerebrospinal fluid of ALS patients [ 124 ].…”

Section: From Ceramide Toward Complex Sphingolipidsmentioning

confidence: 99%

Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy

Tringali

Giussani

2022

IJMS

View full text Add to dashboard Cite

Neurodegenerative disorders (ND) are progressive diseases of the nervous system, often without resolutive therapy. They are characterized by a progressive impairment and loss of specific brain regions and neuronal populations. Cellular and animal model studies have identified several molecular mechanisms that play an important role in the pathogenesis of ND. Among them are alterations of lipids, in particular sphingolipids, that play a crucial role in neurodegeneration. Overall, during ND, ceramide-dependent pro-apoptotic signalling is promoted, whereas levels of the neuroprotective spingosine-1-phosphate are reduced. Moreover, ND are characterized by alterations of the metabolism of complex sphingolipids. The finding that altered sphingolipid metabolism has a role in ND suggests that its modulation might provide a useful strategy to identify targets for possible therapies. In this review, based on the current literature, we will discuss how bioactive sphingolipids (spingosine-1-phosphate and ceramide) are involved in some ND (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis) and their possible involvement in therapies.

show abstract

GBA mutations, glucosylceramide and Parkinson's disease

Cited by 32 publications

References 37 publications

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

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

Bioinformatics Analysis of next generation sequencing data for Risk Prediction in Patients with Type 1 diabetes mellitus

Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy

Contact Info

Product

Resources

About