Serum microRNA Profiling at an Early and Late Stages of Rotenone-Induced Parkinson’s Disease in Rats
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE301539 | GEO | 2025/07/05
REPOSITORIES: GEO
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Project description:Peripheral autonomic nervous system (P-ANS) dysfunction is a critical non-motor phenotype of Parkinson's disease (PD). While the majority of PD cases are sporadic with no identified PD-associated genes involved, epidemiological and animal model studies suggest an association with pesticides and other environmental toxins but underlying cellular mechanisms affecting the human P-ANS is unclear. Here, we mapped the global transcriptome changes in human induced-pluripotent stem cell (iPSC) derived P-ANS sympathetic neurons followed by exposure to the PD-related pesticide, rotenone. Surprisingly, we revealed distinct transcriptome profiles between acute and chronic exposure to rotenone. In the acute stage, there was a down regulation of specific cation channel genes mediating action potential signaling, while in the chronic stage, the human P-ANS neurons exhibited dysregulation of anti-apoptotic and Golgi apparatus-related pathways. Moreover, we identified the sodium voltage-gated channel subunit SCN3A/Nav1.3 as a potential biomarker in human P-ANS neurons associated with PD. Our analysis of the rotenone-altered coding and non-coding genome of human P-ANS neurons may thus provide insight into the pathological signaling events that occur in the sympathetic neurons during PD progression.
2024-06-11 | GSE245060 | GEO
Project description:Rotenone is a naturally occurring toxic substance from the Leguminosa plant and belongs to the group of compounds known as rotenoids (Bové et al., 2005). It is commercially used as a pesticide and is epidemiologically linked to PD. Being lipophilic, rotenone can diffuse across biological membranes in the body and gain entry to all the organs and cells (Bové et al., 2005). Rotenone can bind to complex I of the electron transport chain (ETC) and inhibit the enzymatic activity of the NADH-ubiquinone reductase (Schuler and Casida, 2001). This interferes with the oxidation phosphorylation process, and eventually causes cell damage via oxidative stress. Rotenone may also cause the depolymerisation of microtubules into tubulin monomers (Marshall and Himes, 1978). Accumulation of tubulin monomers is potentially cytotoxic, and it is believed that parkin reverses cytotoxicity by ubiquitinating these monomers and targeting them for proteasome degradation (Ren et al., 2003.). Unfortunately, in PD patients with parkin mutations, this is not possible and tubulin accumulates to harmful levels in the cells. A total of 13 RNA samples were analyzed. Cultured murine primary cortical neurons were treated with 10nM rotenone over a time-course of 8h, 15h and 24h (n=3) in addition to the vehicle control (n=4).
2013-12-31 | E-GEOD-22997 | biostudies-arrayexpress
Project description:Human fibroblasts at different population doublings were treated with low amounts of rotenone (mild stress) and compared to untreated fibroblasts. Two different cell lines were used (MRC-5, HFF). Illumina sequencing (HiSeq2000) was applied to generate 50bp single-end reads. 60 samples: 3 biological replicates for each group: MRC-5 cells at 4 different population doublings (PD) with and without rotenone; HFF cells at 6 different population doublings with and without rotenone
2015-08-26 | E-GEOD-64553 | biostudies-arrayexpress
Project description:Rotenone is a naturally occurring toxic substance from the Leguminosa plant and belongs to the group of compounds known as rotenoids (Bové et al., 2005). It is commercially used as a pesticide and is epidemiologically linked to PD. Being lipophilic, rotenone can diffuse across biological membranes in the body and gain entry to all the organs and cells (Bové et al., 2005). Rotenone can bind to complex I of the electron transport chain (ETC) and inhibit the enzymatic activity of the NADH-ubiquinone reductase (Schuler and Casida, 2001). This interferes with the oxidation phosphorylation process, and eventually causes cell damage via oxidative stress. Rotenone may also cause the depolymerisation of microtubules into tubulin monomers (Marshall and Himes, 1978). Accumulation of tubulin monomers is potentially cytotoxic, and it is believed that parkin reverses cytotoxicity by ubiquitinating these monomers and targeting them for proteasome degradation (Ren et al., 2003.). Unfortunately, in PD patients with parkin mutations, this is not possible and tubulin accumulates to harmful levels in the cells.
2013-12-31 | GSE22997 | GEO
Project description:We aimed to explore the neuroprotective efficacy of Yashtimadhu powder, prepared from the roots of Glycyrrhiza glabra L. (https://mpns.science.kew.org; http://www.ayurveda.hu/api/API-Vol-1.pdf) commonly known as licorice, a known Medhya rasayana in the Indian Ayurvedic texts against Parkinson’s disease. To test the efficacy of Yashtimadhu powder, we used rotenone to generate an in vitro PD model using retinoic acid-differentiated IMR32 cells. Yashtimadhu powder (Lot No.64) was procured from SDP Remedies and Research Centre, Mangalore, India, a GMP-certified Ayurvedic product manufacturer ((http://sdpayurveda.com/products/choorna/yastimadhu-choorna/)The Yashtimadhu neuroprotection was ascertained using cell cytotoxicity, activation of apoptotic proteins and kinases. We used Tandem mass tag (TMT)-lables to understand the differentially regulated proteins across various treatment groups, using Orbitrap Fusion Tribrid mass spectrometer. The mass spectrometry data is acquired in biological duplicates and technical triplicates. We report 4,864 proteins corresponding to 4,783 gene symbols. The proteins were filtered out based technical and biological replicate concordance, thereby reporting 3,720 proteins common among the biological replicates.
2021-09-09 | PXD019672 | Pride
Project description:Physiologically relevant cellular models are critical for understanding complex pathological processes. Parkinsonâs disease (PD) is the second most common neurodegenerative disorder characterised by motor and non-motor symptoms. Several cellular models for PD have been developed to reproduce the abberant biochemical pathways associated with Parkinsonâs disease such as oxidative stress, apoptosis, improper clearance of misfolded proteins and mitochondrial impairment. However, there is still a need for models that effectively recapitulate pathological phenotypes of PD. We previously reported that cells derived from the olfactory epithelium of idiopathic PD patients have altered cellular functions compared with age and gender-matched healthy controls. We also identified an underlying dysregulation of molecular pathways including the Nrf2 pathway in PD hONS cells. Here, we tested the hypothesis that hONS cells derived from PD patients are more vulnerable to extrinsic stressors. We identified that PD-hONS cells are particularly sensitive to mitochondrial and oxidative stress. Notably, PD hONS cells exposed to Rotenone undergo significant apoptosis, show reduced mitochondrial complex I activity and reduced induction of Heat Shock Protein HSP27.
2016-10-04 | E-MTAB-4164 | biostudies-arrayexpress
Project description:The LRRK2 G2019S pathogenic mutation causes LRRK2-associated Parkinson’s disease (L2PD) with incomplete penetrance. LRRK2 non-manifesting carriers (L2NMC) are at PD high risk but predicting pheno-conversion is challenging given the lack of progression biomarkers. To investigate novel biomarkers for PD premotor stages, we performed a longitudinal microRNA (miRNA) assessment of serum samples from G2019S L2NMC followed-up over 8 years. Our cohort consisted of G2019S L2NMC stratified by dopamine transporter single-photon emission computed tomography (DaT-SPECT) into DaT-negative (n=20) and DaT-positive L2NMC (n=20), pheno-converted G2019S L2PD patients (n=20), idiopathic PD (iPD) (n=19), and controls (n=40). We also screened a second cohort of L2PD patients (n=19) and controls (n=20) (Total n=158). Compared to healthy controls, we identified 8 deregulated miRNAs in DaT-negative L2NMC, 6 in DaT-positive L2NMC, and one in L2PD. Between groups, the highest miRNA differences, 24 candidate miRNAs, occurred between DaT-positive L2NMC and L2PD. Longitudinally, we found 11 common miRNAs with sustained variation in DaT-negative and DaT-positive L2NMCs compared to their baselines. Our study identifies novel miRNA alterations in premotor stages of PD co-occurring with progressive DaT-SPECT decline before motor manifestation, whose deregulation seems to attenuate after the diagnosis of L2PD. Moreover, we identified 4 miRNAs with relatively high discriminative ability (AUC=0.82) between non-pheno-converted DaT-positive G2019S carriers and pheno-converted L2PD patients (miR-4505, miR-8069, miR-6125, and miR-451a), which hold potential as early progression biomarkers for PD.
2023-01-06 | GSE221543 | GEO
Project description:Parkinson’s disease (PD) is the most common neurodegenerative movement disorder characterized by a progressive loss of dopamine-containing neurons in the Substantia nigra and the presence of so-called Lewy bodies. The mechanisms underlying disease initiation and development are poorly understood and causative therapies are currently not available. In order to gain insights into the molecular signatures of affected neurons during early stages of Parkinson’s disease, we utilized a Drosophila Parkinson model. We applied the pesticide rotenone to induce Parkinson-like phenotypes in the fly and isolated dopamine containing neurons of animals at a presymptomatic disease stage in order to elucidate their transcriptomic characteristics. In these rotenone treated neurons several gene ontologies, including regulation of cell death, were significantly enriched. Moreover, numerous signaling pathways known to be relevant for cell survival were apparently deregulated in these neurons. While the activities of the MAPK/EGFR- and TGF-β-signaling pathways were enhanced, the performance of the Wnt-pathway was dampened, which may be of central importance for their increased propensity to undergo apoptosis. Thus, further studies involving these pathways may provide new insights into the molecular events underlying pathogenesis and may lead to the identification of new targets for neuroprotective interventions.
2015-12-01 | GSE74247 | GEO
Project description:We investigated an subacute study in male Wistar rats, treated daily with 400 ppm rotenone for 1, 3, or 14 consecutive days, followed by necropsy 24h after the last application. Rotenone is a strong mitochondrial respiratory chain complex I inhibitor. Inhibitors of complex I are suggested to exert anti-tumor activity of those tumors relying on oxidative metabolism and are therefore of interest in oncology research. Nevertheless, the safety profile of these inhibitors needs to be rigorously assessed. Rotenone has shown anti-carcinogenic activity in several studies. In this context we used rotenone in our study as tool compound with the aim to identify suitable biomarker candidates and enhance mechanistic insights into the biologic and cellular effects of complex I inhibitors at the organ level after in vivo treatment. Various parameters, including hematology, clinical chemistry and histopathology, major blood cell population phenotyping using FACS and enzymatic activity assays were measured and/or evaluated. Moreover gene expression profiles were determined to investigate pathways and functions affected by rotenone at the molecular level. As organs, liver, heart and brain stem were chosen due to the high metabolic activity, the high energy demand and due to the known neurotoxic effect of rotenone, respectively. The strongest rotenone-induced effects on gene expression were observed in the liver (1444 deregulated genes) compared to heart (650 deregulated genes) and brain stem (52 deregulated genes). These findings, together with the histopathological results, show that liver is a target organ of rotenone.
2017-01-02 | GSE86352 | GEO