Neuro4PD: An Initial Neurorobotics Model of Parkinson's Disease.
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ABSTRACT:
SUBMITTER: Pimentel JM
PROVIDER: S-EPMC8283825 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: Not available
| S-EPMC6353511 | biostudies-literature
Project description:Early onset Parkinson’s Disease (onset <50 years) accounts for between 10-20 percent of all patients. While some of these cases are associated with specific mutations, the majority are sporadic where the cause is unknown. We generated induced pluripotent stem cells from sporadic early onset patients and differentiated them to dopamine neurons. At early stages in culture (30 days) we found significant elevations in soluble α-synuclein protein levels when compared to controls. This was associated with reductions in lysosomal membrane proteins such as LAMP1 and an increase in phosphorylated protein kinase C-α (p-PKCα). Testing activators of lysosomal function showed that specific phorbal esters reduced both α-synuclein and p-PKCα levels and increased LAMP1 expression. Interestingly, very low doses of the drug PEP005 were able to reduce α-synuclein levels without affecting p-PKCα. Similar effects of PEP005 on α-synuclein expression were seen following infusion into the mouse brain. Our data show that early onset sporadic Parkinson’s Disease can be accurately predicted using a ratio of α-synuclein and p-PKCα in dopamine neural cultures derived from patient iPSC’s and that specific phorbal esters can alter both biomarkers making these drugs promising candidates to treat Parkinson’s Disease.
2019-12-06 | PXD011326 | Pride
Project description:Studying the initial molecular mechanisms of the pathogenesis of Parkinson's disease (PD), primarily in the nigrostriatal dopaminergic system, is one of the priorities in neurology. Of particular interest is elucidating these mechanisms in the preclinical stage of PD, which lasts decades before diagnosis and is therefore not available for study in patients. Therefore, our main goal was to study the initial molecular mechanisms of the pathogenesis of PD in the striatum, the key center for dopamine regulation in motor function, in a mouse model of the earliest preclinical stage of PD, from 1 to 24 h after the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). It was shown that the content of tyrosine hydroxylase (TH), the first enzyme in dopamine synthesis, does not change within 6 h after the administration of MPTP, but decreases after 24 h. In turn, TH activity increases after 1 h, decreases after 3 h, remains at the control level after 6 h, and decreases 24 h after the administration of MPTP. The concentration of dopamine in the striatum gradually decreases after MPTP administration, despite a decrease in its degradation. The identified initial molecular mechanisms of PD pathogenesis are considered as potential targets for the development of preventive neuroprotective treatment.
| S-EPMC10816442 | biostudies-literature
Project description:IntroductionSeveral treatment guidelines for Parkinson's disease (PD) had been proposed in recent decades. The aim of current study was to investigate the initial medication utilized in newly diagnosed PD subjects in Taiwan during an eleven-year period.MethodsA total of 7,550 patients with newly diagnosed Parkinsonism were retrospectively enrolled from the National Health Insurance Research Database of Taiwan from 2000 to 2010. After excluding patients at risk of secondary or atypical Parkinsonism, those never receiving medication or having incomplete data, 1,645 subjects were included. The participants were then divided into four treating regimen groups, namely levodopa (LD) only group, dopamine agonist (DA) only group, LD+DA group, and No-LD, No-DA group. The demographic data and medication retention rate were compared across the four treatment groups.ResultsLD only and No-LD, No-DA regimens were the main initial choice of PD treatment in Taiwan. LD containing drugs were more often prescribed to the elderly population than the other two treatment regimens, while No-LD, No-DA medication was the major initial choice for younger patients. DA only regimen occupied only 3-4% of the initial PD prescriptions and was given predominantly by neurologists. Over the eleven-year period, there is a trend for the middle-aged population to receive medication containing LD as initial treatment. The one year retention rate of anti-Parkinsonism medication was around 30-50% in our population. Age, polypharmacy, change of one-year daily levodopa equivalent dosage and newly onset of dementia, stroke and psychiatric diseases all affect drug compliance in PD patients.ConclusionsThis is the first long-term study to explore initial pharmacotherapies in an Asian PD population. We hope to provide evidence for adjusting government policies and public education of physicians and PD patients in the future.
| S-EPMC4164642 | biostudies-literature
Project description:BackgroundGenetic stratification of Parkinson's disease (PD) patients facilitates gene-tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson's Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize ~10,000 participants.MethodsRecruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a reportable LRRK2 variant, or (3) North African Berber or Ashkenazi Jew. DNA analysis involved up to 3 successive steps: (1) variant (LRRK2) and gene (GBA) screening, (2) panel sequencing of 68 PD-linked genes, and (3) genome sequencing.ResultsInitial data based on the first 1360 participants indicated that the ROPAD enrollment strategy revealed a genetic diagnostic yield of ~14% among a PD cohort from tertiary referral centers.ConclusionsThe ROPAD screening protocol is feasible for high-throughput genetic characterization of PD participants and subsequent prioritization for gene-focused research efforts and clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC8246975 | biostudies-literature
Project description:Parkinson's disease is the second most prevalent neurodegenerative disorder, characterized by the degeneration of dopaminergic neurons. Significant improvements in gait balance, particularly step length and velocity, were revealed by less-invasive wireless cortical stimulation. Transcriptome sequencing was performed to demonstrate the cellular mechanism, specifically targeting the primary motor cortex where the stimulation was applied. Our findings indicated that the differentially expressed genes (DEGs), initially down-regulated following Parkinson's disease induction, were subsequently restored to normal levels after cortical stimulation. We propose these DEGs as a potential target for motor disorder treatment in Parkinson's disease. These genes are implicated in crucial processes such as astrocyte-mediated blood vessel development and microglia-mediated phagocytosis of damaged motor neurons, suggesting their significant roles in improvement of behavior disorder. Moreover, these biomarkers not only facilitate rapid and accurate diagnosis of Parkinson's disease but also assist precision medicine approaches.
2024-07-11 | GSE271930 | GEO
Project description:BackgroundsWe aimed to understand the association between initial vestibular function examination and postural instability (PI) development in Parkinson's disease (PD).MethodsAfter screening 51 PD patients, we divided 31 patients into 2 groups based on the presence of PI at the follow-up visit and compared the clinical features and vestibular-evoked myogenic potential (VEMP) variables.ResultsThe mean values of Hoehn and Yahr stage, Unified Parkinson's Disease Rating Scale (UPDRS) part III, and item 30 (postural stability) of UPDRS were larger in patients with PI at a follow-up visit (p = 0.000, 0.006, 0.048, respectively). In VEMP analyses, the onset latencies of left and right cervical VEMPs were significantly reduced in patients with PI (p = 0.013, 0.040, respectively).ConclusionWe found that the initial VEMP test may be associated with later postural imbalance in PD, suggesting the baseline evaluation may help predict future PI occurrence. A more significant number of patients and more long-term follow-ups are likely to be required for confirmation.
| S-EPMC9570519 | biostudies-literature
Project description:Parkinson's disease is a prevalent neurodegenerative disorder for which there is no cure. The cause of PD symptoms is loss of dopamine neurons in the midbrain, but it is not known why these neurons die. Pesticide exposure is epidemiologically associated with PD, and administration of the organic pesticide rotenone to rats recapitulates most of the behavioral, neurochemical, and neuropathological findings in PD, including specific death of dopamine neurons. We have developed an in vitro model of rotenone toxicity using a dopaminergic cell line (SK-N-MC neuroblastoma cells) that mimics many of the cellular changes seen with in vivo rotenone toxicity and with PD, such as alpha-synuclein aggregation and oxidative damage. We are currently using this simple model to explore mechanisms of dopaminergic neurodegeneration, with our ultimate goal being the discovery of novel mechanisms for dopaminergic neuroprotection in PD. We will examine gene expression profiles of cultured SK-N-MC cells at several time points during rotenone exposure to determine pathways involved in rotenone toxicity and dopaminergic degeneration. We will compare these profiles to baseline profiles of rodent dopaminergic neurons that we have already obtained, as well as to profiles of dopamine neurons from rotenone-treated rats that we will obtain in the near future. We will also compare these data to published results from SN neurons from human PD patients. This technique will not only help us to detect gene expression changes relevant to dopaminergic neurodegeneration in PD, but it will allow us to determine if the SK-N-MC system can be reliably used to screen for neuroprotective therapies for PD. We anticipate that SK-N-MC cells will show a relevant subset of the gene changes seen in dopamine neurons in vivo and that this will guide us in the sorts of mechanisms and drugs that can be screened in this system. Chronic exposure to low levels of rotenone causes changes in gene expression in SK-N-MC cells that sensitize the cells to toxic insults. We also hypothesize that there are several compensatory protective pathways that are stimulated by chronic rotenone, although these pathways are ultimately ineffective at preventing damage. We anticipate that gene expression profiling of rotenone-treated cells over time will suggest several novel strategies for neuroprotective intervention. SK-N-MC cells will be grown in three different media: media only, vehicle (EtOH), and rotenone (5 nM). All current experimental evidence in our lab indicates that vehicle-treated cells are indistinguishable from media-only cells. Rotenone-treated cellls have a stereotypical response in culture. At one week, the only noticed change is an increase in alph-synuclein aggregation. At two weeks, evidence of increased oxidative stress appears (increased protein carbonyls and lipid peroxidation). At four weeks, the cells are markedly sensitized to oxidative challenge with H2O2. Therefore, we will examine gene expression at baseline, and during 1, 2, and 4 weeks of rotenone treatment. Three experiments will be performed, each lasting 4 weeks. For each experiment, three separate dishes of vehicle-treated, and rotenone-treated cells will be harvested at 1, 2, and 4 weeks (18 independent samples). Untreated, media-only cells will be harvested after 1 week in vitro to serve as baseline cells. Total RNA will be isolated. An equal amount of RNA from one dish per experiment per group will be used to compose the final samples. Therefore, each independent sample will consist of RNA from 3 separate experiments. This will allow us to take advantage of a pooling strategy, yet not sacrifice technical and biological replication. 21 samples will be sent to the Consortium. Three will be from untreated cells. Nine will be vehicle-treated at 1, 2, and 4 weeks (3 each). Nine will be rotenone-treated at 1, 2 , and 4 weeks (3 each). Each sample will be labeled and hybridized to one Affymetrix Human Genome U133 Plus 2.0 Gene Chip. With assistance of the consortium, we will analyze the data using the Signifiance Analysis of Microarrays (SAM) program and self-organizing map algorithms.
2009-09-23 | E-GEOD-4773 | biostudies-arrayexpress
Project description:The systemic rotenone model of Parkinson's disease (PD) accurately replicates many aspects of the pathology of human PD and has provided insights into the pathogenesis of PD. The major limitation of the rotenone model has been its variability, both in terms of the percentage of animals that develop a clear-cut nigrostriatal lesion and the extent of that lesion. The goal here was to develop an improved and highly reproducible rotenone model of PD. In these studies, male Lewis rats in three age groups (3, 7 or 12-14 months) were administered rotenone (2.75 or 3.0 mg/kg/day) in a specialized vehicle by daily intraperitoneal injection. All rotenone-treated animals developed bradykinesia, postural instability, and/or rigidity, which were reversed by apomorphine, consistent with a lesion of the nigrostriatal dopamine system. Animals were sacrificed when the PD phenotype became debilitating. Rotenone treatment caused a 45% loss of tyrosine hydroxylase-positive substantia nigra neurons and a commensurate loss of striatal dopamine. Additionally, in rotenone-treated animals, alpha-synuclein and poly-ubiquitin positive aggregates were observed in dopamine neurons of the substantia nigra. In summary, this version of the rotenone model is highly reproducible and may provide an excellent tool to test new neuroprotective strategies.
| S-EPMC2757935 | biostudies-literature
Project description:Cellular toxicities of alpha-synuclein manifest through multiple pathways, including mitochondrial dysfunction and the inhibition of vesicle trafficking. Several defects can be ameliorated by small molecule suppressors that antagonize toxicity in model systems ranging from yeast to neurons. Connections between these distinct pathologies may be central to Parkinson Disease and to therapeutic strategies. First, yeast cultures with 1 or 2 copies of human alpha-synuclein were profiled during a time series of 0 to 6 hours. Second, to investigate any potential rescue of alpha-synuclein toxicity, one of a series of six compounds: compound 1 ((4-(3-iodophenyl)-3,4-dihydrobenzo[h]quinolin-2(1H)-one); compound 2 (4-(3-bromophenyl)-3,4-dihydrobenzo[h]quinolin-2(1H)-one); compound 3 (4-(5-bromo-2-fluorophenyl)-6,7-dimethyl-3,4-dihydro-2(1H)-quinolinone); compound 4 (4-(3-bromo-4-fluorophenyl)-6,7-dimethyl-3,4-dihydro-2(1H)-quinolinone); compound 5 (4-(4-ethyl)-6,7-dimethyl-3,4-dihydro-2(1H)-quinolinone); compound 6 ((4R)-6-bromo-4-(4-ethylphenyl)-3,4-dihydrobenzo[h]quinolin-2(1H)-one); was introduced and the expression profile assayed at 4 hours.
2010-01-04 | GSE11633 | GEO