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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Comparative transcriptome analysis in monocyte-derived macrophages of asymptomatic GBA mutation carriers and patients with GBA-associated Parkinson’s disease

ABSTRACT: We compared transcriptome of monocyte-derived macrophages of 5 patients with GBA-PD (4 L444P/N, 1 N370S/N) and 4 asymptomatic GBA mutation carriers (GBA-carriers) (3 L444P/N, 1 N370S/N) and 4 controls. We also conducted comparative transcriptome analysis for L444P/N only GBA-PD patients and GBA-carriers. Revealed deregulated genes in GBA-PD independently of GBA mutations (L444P or N370S) were involved in immune response, neuronal function. We found upregulated pathway associated with zinc metabolism in L444P/N GBA-PD patients. The potential important role of DUSP1 in the pathogenesis of GBA-PD was suggested.

INSTRUMENT(S): Illumina HiSeq 1500

ORGANISM(S): Homo sapiens

SUBMITTER: Tatiana Usenko

PROVIDER: E-MTAB-11029 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Comparative transcriptome analysis in monocyte-derived macrophages of asymptomatic GBA mutation carriers and patients with GBA-associated Parkinson’s disease

Project description:We compared transcriptome of monocyte-derived macrophages of 5 patients with GBA-PD (4 L444P/N, 1 N370S/N) and 4 asymptomatic GBA mutation carriers (GBA-carriers) (3 L444P/N, 1 N370S/N) and 4 controls. We also conducted comparative transcriptome analysis for L444P/N only GBA-PD patients and GBA-carriers. Revealed deregulated genes in GBA-PD independently of GBA mutations (L444P or N370S) were involved in immune response, neuronal function. We found upregulated pathway associated with zinc metabolism in L444P/N GBA-PD patients. The potential important role of DUSP1 in the pathogenesis of GBA-PD was suggested.

2021-09-29 | GSE184956 | GEO

Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids [2]

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Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids [1]

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Proteomic analysis of GBA iPSC-dopamine neurons

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Role and dysregulation of miRNA in patients with Parkinson’s disease

Project description:Parkinson’s disease (PD) is the most common movement disorder in the aging population, with an estimated prevalence of 1% of people above 60 years old. More recently, PD risk genes, have been found to be regulated by the small non-coding RNAs, (microRNAs or miRNAs), and, as such, may contribute to PD development through a direct regulation on the mitochondrial and immune pathways. Many of these are influenced by epigenetic mechanisms, among which ones mediated by, miRNAs, that regulate gene expression at a post transcriptional level by binding to their 3′ un-translated region (3′ UTR) of target messenger RNAs (mRNAs) inducing mRNA degradation and translational repression. This study aimed to identify and characterize miRNA to evaluate their possible deregulation in PD patients compared to CRTL. In addition, we investigated how specific miRNAs are able to target genes and, thus, to modulate their functions in PD patient. Small RNA expression profiling was performed by next-generation sequencing in PD patients and CTRL after filtered out low-quality reads and trimming the adaptors. The obtained high-quality reads were aligned against the human genome reference.

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microRNA (miRNA) expression profiling of PBMCs of Parkinson's disease (PD) patients and controls

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Single cell sequencing of iPSC-dopamine neurons reconstructs disease progression and identifies HDAC4 as a regulator of Parkinson cell phenotypes

Project description:Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson’s disease (PD) but neuronal cultures are confounded by cellular heterogeneity. By applying high-resolution single cell transcriptomic analyses to Parkinson’s iPSC-derived dopamine neurons carrying the GBA-N370S risk variant, we exploited intra-culture cellular heterogeneity to identify a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Analysis of genes differentially-expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with compounds known to modulate HDAC4 activity upregulated genes early in the DE axis, and corrected Parkinson’s-related cellular phenotypes. Our study demonstrates how single cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets.

2018-10-17 | E-MTAB-7303 | biostudies-arrayexpress

A Gene Expression Phenotype In Lymphocytes From Friedreich’s Ataxia Patients

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Bioengineered models of Parkinson’s Disease using Patient-derived Dopaminergic Neurons exhibit distinct Biological Profiles in a 3D Microenvironment

Project description:Background: Three-dimensional (3D) in vitro culture systems using human induced pluripotent stem cells (hiPSCs) represent impactful platforms to model neurodegenerative disease biology in physiologically relevant microenvironments. Though many successful biomaterials-based 3D model systems have been established for other neurogenerative diseases, such as Alzheimer’s Disease, relatively few exist for Parkinson’s Disease (PD) research. Methods: We employed tissue engineering approaches to construct a 3D silk scaffold-based platform for the culture of hiPSC-dopaminergic (DA) neurons derived from healthy individuals and PD patients harboring LRRK2 G2019S or GBA N370S mutations. We then compared results from protein, gene expression and metabolic analyses obtained from two-dimensional (2D) and 3D culture systems. Results: The 3D platform enabled the formation of dense dopamine neuronal network architectures and developed biological profiles both similar and distinct from 2D culture systems in healthy and PD disease lines. 3D PD cultures showed elevated levels of α-synuclein and alterations in purine metabolite profiles. Furthermore, computational network analysis of transcriptome networks nominated several novel molecular interactions occurring in neurons from patients with mutations in LRRK2 and GBA. Conclusion: The brain-like 3D system presented here is a realistic platform to interrogate molecular mechanisms underlying PD biology. The key advantages of silk-based bioengineering technology include long-term culture and the ability to incorporate multiple brain-relevant cell types to parse cell-cell interactions in development, disease, and aging.

2022-03-16 | GSE172409 | GEO

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