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Transcriptomic alterations in fibroblast from parkinson's disease patients at high glucose levels

ABSTRACT: In this study, we evaluate the hypothesis that molecular pathways in a cell model of Parkinson’s disease (PD) could be altered depending of glucose levels. We cultured fibroblasts from sporadic PD (sPD; n=4), PD patients carrying LRRK2 mutations (LRRK2-PD; n=3) and healthy controls (HC; n=4) at high (25 mM) and low (5 mM) glucose and analysed the transcriptome profile by using whole RNA sequencing. We found 1439 differentially expressed transcripts (DET) comparing HC with overall PD cases. These genes are related with THE gene ontology terms cytosqueleton, cell adhesion, protein translation and ribosomes, mitochondrial electron transport between others, when cultured at 25 mM of glucose. However, at 5 mM there are virtually no gene expression changes in PD compared to controls. When compared between 5 and 25 mM condition separately for each group HC and PD, we found 1482 DET in controls, and 3381 in PD cases, but only found altered significant gene ontology terms in PD. These findings suggest that high glucose levels cause specific molecular changes in fibroblasts which is exacerbated in PD, potentially leading to non adaptive changes. This work emphasizes the importance of energetic balance in PD and the need of further research about the role of glucose levels in clinical studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE82340 | GEO | 2021/12/30

REPOSITORIES: GEO

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Transcriptomic alterations in fibroblast from parkinson's disease patients at high and low glucose levels

Project description:In this study, we evaluate the hypothesis that molecular pathways in a cell model of Parkinson’s disease (PD) could be altered depending of glucose levels. We cultured fibroblasts from sporadic PD (sPD; n=4), PD patients carrying LRRK2 mutations (LRRK2-PD; n=3) and healthy controls (HC; n=4) at high (25 mM) and low (5 mM) glucose and analysed the transcriptome profile by using whole RNA sequencing. We found 1439 differentially expressed transcripts (DET) comparing HC with overall PD cases. These genes are related with THE gene ontology terms cytosqueleton, cell adhesion, protein translation and ribosomes, mitochondrial electron transport between others, when cultured at 25 mM of glucose. However, at 5 mM there are virtually no gene expression changes in PD compared to controls. When compared between 5 and 25 mM condition separately for each group HC and PD, we found 1482 DET in controls, and 3381 in PD cases, but only found altered significant gene ontology terms in PD. These findings suggest that high glucose levels cause specific molecular changes in fibroblasts which is exacerbated in PD, potentially leading to non adaptive changes. This work emphasizes the importance of energetic balance in PD and the need of further research about the role of glucose levels in clinical studies. .

2022-03-30 | GSE167529 | GEO

Transcriptomic alterations in fibroblasts from Parkinson's disease patients carrying Parkin mutations

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Metabolic Profiling of CSF from People Suffering from Sporadic and LRRK2 Parkinson's Disease: A Pilot Study

Project description:CSF from unique groups of Parkinson's disease (PD) patients was biochemically profiled to identify previously unreported metabolic pathways linked to PD pathogenesis, and novel biochemical biomarkers of the disease were characterized. Utilizing both 1H NMR and DI-LC-MS/MS we quantitatively profiled CSF from patients with sporadic PD (n = 20) and those who are genetically predisposed (LRRK2) to the disease (n = 20), and compared those results with age and gender-matched controls (n = 20). Further, we systematically evaluated the utility of several machine learning techniques for the diagnosis of PD. 1H NMR and mass spectrometry-based metabolomics, in combination with bioinformatic analyses, provided useful information highlighting previously unreported biochemical pathways and CSF-based biomarkers associated with both sporadic PD (sPD) and LRRK2 PD. Results of this metabolomics study further support our group's previous findings identifying bile acid metabolism as one of the major aberrant biochemical pathways in PD patients. This study demonstrates that a combination of two complimentary techniques can provide a much more holistic view of the CSF metabolome, and by association, the brain metabolome. Future studies for the prediction of those at risk of developing PD should investigate the clinical utility of these CSF-based biomarkers in more accessible biomatrices. Further, it is essential that we determine whether the biochemical pathways highlighted here are recapitulated in the brains of PD patients with the aim of identifying potential therapeutic targets.

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Expression mRNA data from mouse blood samples measured using the NanoString nCounter platform

Project description:Background: The diagnosis of Parkinson’s disease (PD) is usually not established until advanced neurodegeneration leads to clinically detectable symptoms. Previous blood PD transcriptome studies show low concordance, possibly due to the use of microarray technology, which has high measurement variation. The Leucine-rich repeat kinase 2 (LRRK2) G2019S mutation predisposes to PD. Using preclinical and clinical studies, we sought to develop a novel statistically motivated transcriptomic-based approach to identify a molecular signature in the blood of Ashkenazi Jewish PD patients including LRRK2 mutation carriers. Methods: Using a digital gene expression platform to quantify 175 mRNA markers with low coefficients of variation (CV), we first compared whole blood transcript levels in mouse models 1) over-expressing wild-type (WT) LRRK2, 2) overexpressing G2019S LRRK2, 3) lacking LRRK2 (knockout), 4) and in WT controls. We then studied an Ashkenazi Jewish cohort of 34 symptomatic PD patients (both WT LRRK2 and G2019S LRRK2) and 32 asymptomatic controls. Results: The expression profiles distinguished the 4 mouse groups with different genetic background. In patients, we detected significant differences in blood transcript levels both between individuals differing in LRRK2 genotype and between PD patients and controls. Discriminatory PD markers included genes associated with innate and adaptive immunity and inflammatory disease. Notably, gene expression patterns in L-DOPA-treated PD patients were significantly closer to those of healthy controls in a dose-dependent manner. Conclusions: We identify whole blood low CV mRNA signatures correlating with LRRK2 genotype and with PD disease state. This approach may provide insight into pathogenesis and a route to early disease detection.

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Expression mRNA data from human blood samples measured using the NanoString nCounter platform

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Genome-wide expression profiling of the LRRK2-G2019S mutation in hNES cells

Project description:Parkinson’s disease (PD) has a neuro-developmental component with multiple genetic predispositions. The most prevalent mutation, LRRK2-G2019S is linked to familial and sporadic PD. Based on the multiple origins of PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patient genetic background act as susceptibility factors for developing PD. To assess the developmental component of LRRK2-G2019S pathogenesis, we used 19 human iPSC-derived neuroepithelial stem cell lines (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal. Within patients, phenotypes were only partly LRRK2-G2019S dependent, suggesting Parkinson’s disease (PD) has a neuro-developmental component with multiple genetic predispositions. The most prevalent mutation, LRRK2-G2019S is linked to familial and sporadic PD. Based on the multiple origins of PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patient genetic background act as susceptibility factors for developing PD. To assess the developmental component of LRRK2-G2019S pathogenesis, we used 19 human iPSC-derived neuroepithelial stem cell lines (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal. Within patients, phenotypes were only partly LRRK2-G2019S dependent, suggesting a significant contribution of the genetic background. We identified Serine racemase (SRR) as a novel patient-specific, developmental, genetic modifier contributing to the abberant phenotypes. Its enzymatic product, D-Serine, rescued altered NESC renewal. Susceptibility factors in the genetic background, such as SRR, could be new targets for early PD diagnosis and treatment.

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Project description:LRRK2 mutations are the most common genetic cause of Parkinson’s disease (PD). We performed a whole-genome RNA profiling of putamen tissue from idiopathic PD (IPD), LRRK2-associated PD (G2019S mutation), neurologically healthy controls and one asymptomatic LRRK2 mutation carrier, by using the Genechip Human Exon 1.0-ST Array. The differentially expressed genes found in IPD revealed an alteration of biological pathways related to long term potentiation (LTP), GABA receptor signalling, and calcium signalling pathways, among others. These pathways are mainly related with cell signalling cascades and synaptic plasticity processes. They were also altered in the asymptomatic LRRK2 mutation carrier but not in the LRRK2-associated PD group. The expression changes seen in IPD might be attributed to an adaptive consequence of a dysfunction in the dopamine transmission. The lack of these altered molecular pathways in LRRK2-associated PD patients suggests that these cases could show a different molecular response to dopamine transmission impairment.

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Gene and microRNA transcriptome analysis of Parkinson's related LRRK2 mouse models

Project description:Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial and sporadic ParkinsonM-bM-^@M-^Ys disease (PD). Here, we investigated in parallel gene and microRNA transcriptome profiles of three different LRRK2 mouse models. Striatal tissue was isolated from adult LRRK2 knockout mice, as well as mice expressinghuman LRRK2 wildtype (hLRRK2-WT) or PD-associated R1441G mutation (hLRRK2-R1441G). We used microarraya to measure gene and microRNA expression levels in various LRRK2 mouse models. LRRK2 wildtype and knockout mice were bred on a C57BL/6 background. LRRK2 non-transgenic and hLRRK2 transgenic mice were bred on a FVB/N background.

2013-11-22 | E-GEOD-52584 | biostudies-arrayexpress

RNA-Seq of LRRK2 G2019S Parkinson’s iPSC-derived astrocytes

Project description:Non-neuronal cell types such as astrocytes can contribute to Parkinson’s disease (PD) pathology. The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is one of the most common known causes of familial PD. To characterize its effect on astrocytes, we developed a protocol to produce midbrain-patterned astrocytes from human induced pluripotent stem cells (iPSCs) derived from PD LRRK2 G2019S patients and healthy controls. In order to understand the effect of this mutation on astrocyte function, we compared the gene expression profiles of iPSC-derived midbrain-patterned astrocytes from PD patients with those from healthy controls.

2018-09-22 | GSE120306 | GEO

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Project description:Emerging evidence suggest that Parkinson's disease (PD), besides being an age-associated disorder, might also have a neurodevelopment component. Disruption of mitochondrial homeostasis has been highlighted as a crucial cofactor in its etiology. Here, we show that PD patient-specific human neuroepithelial stem cells (NESCs) carrying the LRRK2-G2019S mutation recapitulate key mitochondrial defects previously described only in differentiated dopaminergic neurons. By combining high-content imaging approaches, 3D image analysis, and functional mitochondrial readouts we show that LRRK2-G2019S mutation caused aberrations in mitochondrial morphology and functionality compared to isogenic controls. LRRK2-G2019S NESCs displayed an increased number of mitochondria compared to isogenic control lines. However, these mitochondria were more fragmented and exhibited decreased membrane potential. Coherently, the release of total and mitochondrial redox oxidative species increased in LRRK2-G2019S NESC compared to controls. Functional alterations in LRRK2-G2019S cultures were also accompanied by a reduced mitophagic clearance via lysosomes. These findings support the hypothesis that preceding mitochondrial developmental defects contribute to the manifestation of the PD pathology later in life.

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