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GBA1 interactome for understanding pathological mechanisms

ABSTRACT: Compound heterozygous or homozygous GBA1 mutations lead to Gaucher disease. Furthermore, GBA1 mutations are the most frequent risk factor for Parkinsonâ€™s disease. To get a better understanding of the pathological mechanisms, we generated inducible V5-Flag-Tag, V5-Flag-tagged WT, E326K and L444P mutant Flp-Inâ„¢T-RExâ„¢-HEK293 and performed interatomic analysis.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Frank Stein

LAB HEAD: Michela Deleidi

PROVIDER: PXD032155 | Pride | 2023-05-10

REPOSITORIES: pride

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			Action	DRS
	F084709.dat	Other
	F084712.dat	Other
	F084713.dat	Other
	F084715.dat	Other
	F084717.dat	Other

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Publications

Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.

Baden Pascale P Perez Maria Jose MJ Raji Hariam H Bertoli Federico F Kalb Stefanie S Illescas María M Spanos Fokion F Giuliano Claudio C Calogero Alessandra Maria AM Oldrati Marvin M Hebestreit Hannah H Cappelletti Graziella G Brockmann Kathrin K Gasser Thomas T Schapira Anthony H V AHV Ugalde Cristina C Deleidi Michela M

Nature communications 20230406 1

Mutations in GBA1, the gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson's disease (PD). Here, we employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into ...[more]

PMID: 37024507

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Dimethyl labeling-based quantitative PTM proteomic analysis of drought-regulated phosphoproteomes in soybean drought-tolerant cultivar

Project description:The isotopic dimethyl labeling-based quantitative post-translational modification proteomics was applied to study the phosphoproteomic changes associated with the drought responses of two contrasting soybean cultivars. A total of 9,457 non-redundant, unambiguous, label-independent and repeatable phosphopeptides were subsequently identified from six experimental replicates, corresponding to 9,234 of deduced unique phosphoproteins. These soybean proteins contain a total of 20,880 phosphosites, 84.9% of which were found to be novel phosphosites of the soybean phosphoproteome. The overly post-translationally modified proteins is 2.05% of the phosphoproteins identified. Most of these extensively phosphorylated proteins are photoreceptors, mRNA-, histone- and phospholipid-binding as well as serine/threonine/tyrosine protein kinase/phosphatases. The subgroup population distribution of phosphoproteins over the number of the phosphosite of phosphoprotein follows the exponential decay law, Y=4.13e^(-0.098X)-0.04. From 218 significantly regulated unique phosphopeptide groups, 188 significantly regulated phosphoproteins were found, and they are enriched in biological functions of water transport and deprivation, methionine metabolic process, photosynthesis/light reaction, and response to cadmium ion, osmotic stress and ABA under drought treatment. A total of 15 and 20 drought-tolerant cultivar significantly regulated phosphoproteins are transcription factors and protein kinases/phosphatases, respectively. More than 50% of these phosphoproteins are considered to be novel regulatory components, presumably mediating the development of the soybean drought tolerance under water deprivation process. The association of five randomly selected phosphoproteins with the drought response was corroborated with the qRT-PCR method.

2023-05-10 | PXD022806 | Pride

Combining FAIMS based Glycoproteomic and DIA Proteomic of reveals widespread proteome alteration in response to changes in N. gonorrhoeae glycosylation.- FAIMS pglO alleles

Project description:Protein glycosylation is increasingly recognized as a common protein modification across bacterial species. Within members of the Neisseria genus O-linked protein glycosylation plays important roles in virulence and antigenic variation yet our understanding of the substrates of glycosylation are limited. Recently it was identified that even closely related Neisserial species can possess O-oligosaccharyltransferases, pglOs, that possess varying glycosylation specificities suggesting that distinct targeting activities may impact both the glycoprotome as well as the proteome of Neisserial species. Within this work we explore this concept using of Field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS) fractionation and Data-Independent Acquisition (DIA) to allow the characterization of differences in the glycoproteomes and proteomes within N. gonorrhoeae strains expressing differing pglO alleles. We demonstrate the utility of FAIMS to expand the known glycoproteome of N. gonorrhoeae and enable comparative glycoproteomics of a recently reported panel of N. gonorrhoeae strains expressing different pglO allelic chimeras (15 pglO enzymes) with unique substrate targeting activities. Combining glycoproteomic insights with DIA proteomics we demonstrate that alterations within pglO alleles have widespread impacts on the proteome of N. gonorrhoeae yet lead to minimal effects on the abundance of glycoproteins. Additionally, while DIA analysis can allow occupancy to be inferred by the absence or presence of peptides known to be modified, we observe a poor correlation between DIA measurements of non-modified versions of glycopeptides and glycoproteomic analysis. Combined this work expands our understanding of the N. gonorrhoeae glycoproteome and supports that the expression of different pglO alleles appears to drive proteomic changes independent of the glycoproteins targeted for glycosylation.

2024-02-01 | PXD044666 | Pride

Proteomic analysis of primary human microvascular endothelial cells (HMVECs) stimulated for 24â€‰h with either 50 ï�g/mL recombinant Fibrillin-1 C-terminal fragment or 25â€‰ng/ml VEGF-A compared to unstimulated cells.

Project description:Mutations in the fibrillin-1 gene result in cardiovascular, ocular, and skeletal abnormalities in Marfan syndrome. Here we show that a fibrillin-1 mutation also alters the neovessel formation. In the mouse retina vascularization model, fibrillin-1 is detected at the basement membrane underlying the angiogenic front and around arterioles. In Fbn1C1041G/+ mice, a model of Marfan disease, the microvasculature is altered at these sites. At the front, endothelial tip-cell sprouting and branching are decreased, and we show that mutant fibrillin-1 delays angiogenesis by affecting Notch signalling. Supplying the growing vasculature of Fbn1C1041G/+ mice with a C-terminal fragment of fibrillin-1 corrects all defects. In vitro, the C-terminal fragment of fibrillin-1 also displays pro-angiogenic activities on microvascular endothelial cell. Our data establish that fibrillin-1 performs essential functions in microvessel formation and integrity and that mutant fibrillin-1-induced defects can be rescued pharmacologically.

2023-05-31 | PXD029834 | Pride

Diagnosis of hepatocellular adenomas and malignancy determination by proteomic patterns matching (4)

Project description:Biopsies are underrated and underused and our goal was to demonstrate that their inherent expression proteomic pattern could give them an added value for diagnosis. As proof of concept, we used as model hepatocellular adenomas (HCA), well characterized benign liver tumors. From a collection of 260 cases, we selected 55 typical cases to build the first HCA proteomic database. Biopsies proteomic patterns allowed HCA classification, even for complex cases. In addition, these data gave access to a malignancy pattern identifying the HCA transformation. This pioneering work proposes a proteomic based machine learning tool, operational on fixed biopsies, to improve HCA diagnosis and therefore patientâ€™s management.

2021-06-11 | PXD022844 | Pride

Diagnosis of hepatocellular adenomas and malignancy determination by proteomic patterns matching (1)

2021-06-11 | PXD022835 | Pride

Diagnosis of hepatocellular adenomas and malignancy determination by proteomic patterns matching (3)

2021-06-11 | PXD022839 | Pride

Diagnosis of hepatocellular adenomas and malignancy determination by proteomic patterns matching (2)

2021-06-11 | PXD022837 | Pride

ChIP-seq of MOZ (Flag-V5-BIO tagged) in mouse mouse craniofacial development

Project description:Carboxy-terminally tagged MOZ (Flag-V5-BIO tagged) was detected by ChIP-seq using anti-V5 antibody (Sigma, A7345) to precipitate chromatin associated with MOZ

2019-07-23 | GSE134607 | GEO

GBA1 regulates the CLEAR network through Calcineurin and TFEB in cellular models of Parkinson´s disease

Project description:The GBA1 gene encodes the lysosomal enzyme acid-β-glucocerebrosidase (GCase). GBA1 mutations cause the lysosomal storage disorder Gaucher disease (GD) and are a genetic risk factor for Parkinson´s disease (PD). Many GBA1 mutations cause aberrant GCase folding and processing but how these impinge on PD pathogenesis remains unclear. We addressed GCase functions in human dopaminergic (DA) neurons derived from engineered GBA1-deficient (GBA1-/-) embryonic stem cells (hESCs) and GBA1N370S PD patient-derived induced pluripotent cells (hiPSCs). GBA1-mutant DA neurons displayed aberrant morphologies and gene expression that were rescued by recombinant GCase treatment. GBA1-/- neurons have hyperactive Calcineurin (CaN) and nuclear localization of the Transcription Factor EB (TFEB). Expression of TFEB targets and lysosomal CLEAR network components were increased in GBA1-/- DA neurons and rescued by GCase replacement and CaN inhibition. Our findings reveal a link between increased CaN activity and loss of GCase, providing a mechanism for the disturbed lysosomal/autophagy pathways in GBA1-associated PD.

2022-12-31 | GSE118511 | GEO

DiGly_Analysis_RAD18_RAD6_with/without_MAGEA4

Project description:Auto-ubiquitination assay performed in which the E3 ligase complex RAD18-RAD6 was incubated with E1 and ubiquitin in the presence/absence of MAGEA4for 1 hour at 37C. All proteins were purified from E.coli. Samples were loaded and run onto a precast SDS PAGE gel, which was stained with Coomasie. Approximately 20ug of RAD18-RAD6 was used for the assay.

2024-02-20 | PXD047850 | Pride

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