scholarly journals Metabolic response to Parkinson's disease recapitulated by the haploinsufficient diploid yeast cells hemizygous for the adrenodoxin reductase gene

2019 ◽  
Vol 15 (5) ◽  
pp. 340-347
Author(s):  
Duygu Dikicioglu ◽  
James W. M. T. Coxon ◽  
Stephen G. Oliver
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Metabolic Response ◽  
Early Stage ◽  
Disease Model ◽  
Yeast Cells ◽  
Iron Assimilation ◽  
Reductase Gene ◽  
Adrenodoxin Reductase ◽  
Tyrosine Biosynthesis

ARH1-impaired yeast reorganises iron assimilation and tyrosine biosynthesis, suggesting its potential as early-stage Parkinson's disease model, since patient metabolic responses implicate interconnection between these pathways.

scholarly journals Metabolic response to Parkinson’s disease recapitulated by the haploinsufficient phenotype of diploid yeast cells hemizygous for the adrenodoxin reductase gene

2019 ◽  
Author(s):  
Duygu Dikicioglu ◽  
James W. M. T. Coxon ◽  
Stephen G. Oliver
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cellular Response ◽  
Iron Homeostasis ◽  
Metabolic Response ◽  
Single Copy ◽  
Yeast Cells ◽  
Dopaminergic Neurodegeneration ◽  
Iron Assimilation ◽  
Adrenodoxin Reductase

AbstractAdrenodoxin reductase, a widely conserved mitochondrial P450 protein, catalyses essential steps in steroid hormone biosynthesis and is highly expressed in the adrenal cortex. The yeast adrenodoxin reductase homolog, Arh1p, is involved in cytoplasmic and mitochondrial iron homeostasis and is required for activity of enzymes containing an Fe-S cluster. In this paper, we investigated the response of yeast to the loss of a single copy of ARH1, an oxidoreductase of the mitochondrial inner membrane, which is among the few mitochondrial proteins that is essential for viability in yeast. The phenotypic, transcriptional, proteomic, and metabolic landscape indicated that Saccharomyces cerevisiae successfully adapted to this loss, displaying an apparently dosage-insensitive cellular response. However, a considered investigation of transcriptional regulation in ARH1-impaired yeast highlighted that a significant hierarchical reorganisation occurred, involving the iron assimilation and tyrosine biosynthetic processes. The interconnected roles of the iron and tyrosine pathways, coupled with oxidative processes, are of interest beyond yeast since they are involved in dopaminergic neurodegeneration associated with Parkinson’s disease. The identification of similar responses in yeast suggest that this simple eukaryote could have potential as a model system for investigating the regulatory mechanisms leading to the initiation and progression of early disease responses in humans.

scholarly journals The Effect of Human Umbilical Cord Mesenchymal Stromal Cells in Protection of Dopaminergic Neurons from Apoptosis by Reducing Oxidative Stress in the Early Stage of a 6-OHDA-Induced Parkinson’s Disease Model

2019 ◽  
Vol 28 (1_suppl) ◽  
pp. 87S-99S ◽  
Author(s):  
Heng Chi ◽  
Yunqian Guan ◽  
Fengyan Li ◽  
Zhiguo Chen
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Early Stage ◽  
Disease Model ◽  
Human Umbilical Cord ◽  
And Oxidative Stress ◽  
Neuron Apoptosis

Oxidative stress is an important cause of dopaminergic (DA) neuron apoptosis in Parkinson’s disease (PD). Mesenchymal stromal cells (MSCs) possess antioxidative features. In this study, we investigated whether MSCs could reduce oxidative stress and protect DA neurons from apoptosis by intravenous (I.V.) injection in the early stage of a 6-hydroxydopamine (6-OHDA)-induced PD model. MSCs were injected into the tail vein of mice, and behavioral tests, immunofluorescence staining, western blot, and oxidative stress levels were assessed at different time points. After 6-OHDA exposure, DA neuron apoptosis was detected, together with severe oxidative stress in brain and periphery. Compared with the non-transplanted sham controls, motor function in the 6-OHDA-lesioned group after I.V. injection of MSCs was significantly improved, and the levels of DA neuron apoptosis and oxidative stress decreased. The results demonstrate that MSCs can rescue DA neurons from ongoing apoptosis by reducing oxidative stress, and provide insights on developing new therapeutic strategies to offset the degenerative process of PD.

Association of the Non-Motor Burden with Patterns of Striatal Dopamine Loss in de novo Parkinson’s Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 1541-1549
Author(s):  
Seok Jong Chung ◽  
Sangwon Lee ◽  
Han Soo Yoo ◽  
Yang Hyun Lee ◽  
Hye Sun Lee ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
De Novo ◽  
Early Stage ◽  
Striatal Dopamine ◽  
Motor Deficits ◽  
Dopamine Depletion ◽  
Severe Motor ◽  
Severe Group ◽  
Striatal Dopamine Depletion

Background: Striatal dopamine deficits play a key role in the pathogenesis of Parkinson’s disease (PD), and several non-motor symptoms (NMSs) have a dopaminergic component. Objective: To investigate the association between early NMS burden and the patterns of striatal dopamine depletion in patients with de novo PD. Methods: We consecutively recruited 255 patients with drug-naïve early-stage PD who underwent 18F-FP-CIT PET scans. The NMS burden of each patient was assessed using the NMS Questionnaire (NMSQuest), and patients were divided into the mild NMS burden (PDNMS-mild) (NMSQuest score <6; n = 91) and severe NMS burden groups (PDNMS-severe) (NMSQuest score >9; n = 90). We compared the striatal dopamine transporter (DAT) activity between the groups. Results: Patients in the PDNMS-severe group had more severe parkinsonian motor signs than those in the PDNMS-mild group, despite comparable DAT activity in the posterior putamen. DAT activity was more severely depleted in the PDNMS-severe group in the caudate and anterior putamen compared to that in the PDMNS-mild group. The inter-sub-regional ratio of the associative/limbic striatum to the sensorimotor striatum was lower in the PDNMS-severe group, although this value itself lacked fair accuracy for distinguishing between the patients with different NMS burdens. Conclusion: This study demonstrated that PD patients with severe NMS burden exhibited severe motor deficits and relatively diffuse dopamine depletion throughout the striatum. These findings suggest that the level of NMS burden could be associated with distinct patterns of striatal dopamine depletion, which could possibly indicate the overall pathological burden in PD.

Gene expression analysis in modeling Parkinson’s disease

2020 ◽  
pp. 103-104
Author(s):  
М.М. Руденок ◽  
А.Х. Алиева ◽  
А.А. Колачева ◽  
М.В. Угрюмов ◽  
П.А. Сломинский ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Stage ◽  
Systemic Disease ◽  
Molecular Genetic ◽  
Presymptomatic Stage ◽  
Whole Transcriptome Analysis ◽  
Whole Transcriptome ◽  
The Brain ◽  
Transcriptome Level

Несмотря на очевидный прогресс, достигнутый в изучении молекулярно-генетических факторов и механизмов патогенеза болезни Паркинсона (БП), в настоящее время стало ясно, что нарушения в структуре ДНК не описывают весь спектр патологических изменений, наблюдаемых при развитии заболевания. В настоящее время показано, что существенное влияние на патогенез БП могут оказывать изменения на уровне транскриптома. В работе были использованы мышиные модели досимптомной стадии БП, поздней досимптомной и ранней симптомной (РСС) стадиями БП. Для полнотранскриптомного анализа пулов РНК тканей черной субстанции и стриатума мозга мышей использовались микрочипы MouseRef-8 v2.0 Expression BeadChip Kit («Illumina», США). Полученные данные указывают на последовательное вовлечение транскриптома в патогенез БП, а также на то, что изменения на транскриптомном уровне процессов транспорта и митохондриального биогенеза могут играть важную роль в нейродегенерации при БП уже на самых ранних этапах. Parkinson’s disease (PD) is a complex systemic disease, mainly associated with the death of dopaminergic neurons. Despite the obvious progress made in the study of molecular genetic factors and mechanisms of PD pathogenesis, it has now become clear that violations in the DNA structure do not describe the entire spectrum of pathological changes observed during the development of the disease. It has now been shown that changes at the transcriptome level can have a significant effect on the pathogenesis of PD. The authors used models of the presymptomatic stage of PD with mice decapitation after 6 hours (6 h-PSS), presymptomatic stage with decapitation after 24 hours (24 h-PSS), advanced presymptomatic (Adv-PSS) and early symptomatic (ESS) stages of PD. For whole transcriptome analysis of RNA pools of the substantia nigra and mouse striatum, the MouseRef-8 v2.0 Expression BeadChip Kit microchips (Illumina, USA) were used. As a result of the analysis of whole transcriptome data, it was shown that, there are a greater number of statistically significant changes in the tissues of the brain and peripheral blood of mice with Adv-PSS and ESS models of PD compared to 6 h-PSS and 24 h-PSS models. In general, the obtained data indicate the sequential involvement of the transcriptome in the pathogenesis of PD, as well as the fact that changes at the transcriptome level of the processes of transport and mitochondrial biogenesis can play an important role in neurodegeneration in PD at an early stage.

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