scholarly journals Mechanistic model-driven exometabolomic characterisation of human dopaminergic neuronal metabolism

2021 ◽  
Author(s):  
German Preciat ◽  
Edinson L. Moreno ◽  
Agnieszka Wegrzyn ◽  
Cornelius C.W. Willacey ◽  
Jennifer Modamio ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Mechanistic Model ◽  
Metabolic Dysfunction ◽  
Spearman Rank ◽  
Model Driven ◽  
Cellular Models ◽  
Neuronal Metabolism

Patient-derived cellular models are a powerful approach to study human disease, especially neurodegenerative diseases, such as Parkinson's disease, where affected primary neurons, e.g., substantia nigra dopaminergic neurons, are almost inaccessible. Starting with a comprehensive generic reconstruction of human metabolism, Recon3D, we generated a high-quality, constraint-based, genome-scale, in silico model of human dopaminergic neuronal metabolism (iDopaNeuro1). It is a synthesis of extensive manual curation of the biochemical literature on neuronal metabolism, together with novel, quantitative, transcriptomic and targeted exometabolomic data from human stem cell-derived, midbrain-specific, dopaminergic neurons in vitro. Thermodynamic constraint-based modelling with iDopaNeuro1 is qualitatively accurate (92% correct) and quantitatively accurate (Spearman rank 0.7) at predicting metabolite secretion or uptake, given quantitative exometabolomic constraints on uptakes, or secretions, respectively. iDopaNeuro1 is also qualitatively accurate at predicting the consequences of metabolic perturbations, e.g., complex I inhibition (Spearman rank 0.69) in a manner consistent with literature on monogenic mitochondrial Parkinson's disease. The iDopaNeuro1 model provides a foundation for a quantitative systems biochemistry approach to metabolic dysfunction in Parkinson's disease. Moreover, the plethora of novel mathematical and computational approaches required to develop it are generalisable to study any other disease associated with metabolic dysfunction.

scholarly journals Automated microuidic cell culture of stem cell derived dopaminergic neurons in Parkinson’s disease

2017 ◽  
Author(s):  
Khalid I.W. Kane ◽  
Edinson Lucumi Moreno ◽  
Siham Hachi ◽  
Moriz Walter ◽  
Javier Jarazo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Cell Culture ◽  
Parkinson's Disease ◽  
Stem Cell ◽  
Dopaminergic Neurons ◽  
Disease Patient ◽  
Motor Dysfunction ◽  
Patient Specific ◽  
Cellular Models

AbstractParkinson’s disease is a slowly progressive neurodegenerative disease characterised by dysfunction and death of selectively vulnerable midbrain dopaminergic neurons leading mainly to motor dysfunction, but also other non-motor symptoms. The development of human in vitro cellular models with similar phenotypic characteristics to selectively vulnerable neurons is a major challenge in Parkinson’s disease research. We constructed a fully automated cell culture platform optimised for long-term maintenance and monitoring of induced pluripotent stem cell derived neurons in three dimensional microfluidic cell culture devices. The system can be flexibly adapted to various experimental protocols and features time-lapse imaging microscopy for quality control and electrophysiology monitoring to assess neuronal activity. Using this system, we continuously monitored the differentiation of Parkinson’s disease patient derived human neuroepithelial stem cells into midbrain specific dopaminergic neurons. Calcium imaging confirmed the electrophysiological activity of differentiated neurons and immunostaining confirmed the efficiency of the differentiation protocol. This system is the first example of a fully automated Organ-on-a-Chip culture and enables a versatile array of in vitro experiments for patient-specific disease modelling.

scholarly journals Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

2021 ◽  
pp. 1-16
Author(s):  
Alison Fellgett ◽  
C. Adam Middleton ◽  
Jack Munns ◽  
Chris Ugbode ◽  
David Jaciuch ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Genetic Interaction ◽  
In Vitro Assays ◽  
Rab Proteins ◽  
Circadian Activity ◽  
Loss Of Function ◽  
Lrrk2 G2019s

Background: Inherited mutations in the LRRK2 protein are the common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. Objective: To determine if Rab10 is necessary for LRRK2-induced pathophysiological responses in the neurons that control movement, vision, circadian activity, and memory. These four systems were chosen because they are modulated by dopaminergic neurons in both humans and flies. Methods: LRRK2-G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, retinal neurophysiology, circadian activity pattern (‘sleep’), and courtship memory determined in aged flies. Results: Rab10 loss-of-function rescued LRRK2-G2019S induced bradykinesia and retinal signaling deficits. Rab10 knock-down, however, did not rescue the marked sleep phenotype which results from dopaminergic LRRK2-G2019S. Courtship memory is not affected by LRRK2, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons. Conclusion: We conclude that, in Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson’s disease.

scholarly journals Neuroprotective Effect of Optimized Yinxieling Formula in 6-OHDA-Induced Chronic Model of Parkinson’s Disease through the Inflammation Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Renrong Wei ◽  
Cuiping Rong ◽  
Qingfeng Xie ◽  
Shouhai Wu ◽  
Yuchao Feng ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Calcium Binding ◽  
Dopaminergic Neurons ◽  
Neuroprotective Effect ◽  
Interleukin 1 ◽  
Mrna Levels ◽  
Cox 2

Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN)-striatum circuit, which is associated with glial activation and consequent chronic neuroinflammation. Optimized Yinxieling Formula (OYF) is a Chinese medicine that exerts therapeutical effect and antiinflammation property on psoriasis. Our previous study has proven that pretreatment with OYF could regulate glia-mediated inflammation in an acute mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Given that PD is a chronic degeneration disorder, this study applied another PD animal model induced by striatal injection of 6-hydroxydopamine (6-OHDA) to mimic the progressive damage of the SN-striatum dopamine system in rats. The OYF was administrated in the manner of pretreatment plus treatment. The effects of the OYF on motor behaviors were assessed with the apomorphine-induced rotation test and adjusting steps test. To confirm the effect of OYF on dopaminergic neurons and glia activation in this model, we analyzed the expression of tyrosine hydroxylase (TH) and glia markers, ionized calcium-binding adapter molecule 1 (Iba-1), and glial fibrillary acidic protein (GFAP) in the SN region of the rat PD model. Inflammation-associated factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), were further evaluated in this model and in interferon-γ- (INF-γ-) induced murine macrophages RAW264.7 cells. The results from the in vivo study showed that OYF reversed the motor behavioral dysfunction in 6-OHDA-induced PD rats, upregulated the TH expression, decreased the immunoreactivity of Iba-1 and GFAP, and downregulated the mRNA levels of TNF-α and COX-2. The OYF also trended to decrease the mRNA levels of IL-1β and iNOS in vivo. The results from the in vitro study showed that OYF significantly decreased the mRNA levels of TNF-α, IL-1β, IL-6, iNOS, and COX-2. Therefore, this study suggests that OYF exerts antiinflammatory effects, which might be related to the protection of dopaminergic neurons in 6-OHDA-induced chronic neurotoxicity.

scholarly journals Loss of SATB1 Induces a p21 Dependent Cellular Senescence Phenotype in Dopaminergic Neurons

2018 ◽  
Author(s):  
Markus Riessland ◽  
Benjamin Kolisnyk ◽  
Tae Wan Kim ◽  
Jia Cheng ◽  
Jason Ni ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cellular Senescence ◽  
Dopaminergic Neurons ◽  
Dna Binding Protein ◽  
Dopamine Neurons ◽  
Human Stem Cell ◽  
Transcriptional Program

AbstractCellular senescence is a mechanism used by mitotic cells to prevent uncontrolled cell division. As senescent cells persist in tissues, they cause local inflammation and are harmful to surrounding cells, contributing to aging. Generally, neurodegenerative diseases, such as Parkinson‘s, are disorders of aging. The contribution of cellular senescence to neurodegeneration is still unclear. SATB1 is a DNA binding protein associated with Parkinson’s disease. We report that SATB1 prevents cellular senescence in post-mitotic dopaminergic neurons. Loss of SATB1 causes activation of a cellular senescence transcriptional program in dopamine neurons, both in human stem cell-derived dopaminergic neurons and in mice. We observed phenotypes which are central to cellular senescence in SATB1 knockout dopamine neurons in vitro and in vivo. Moreover, we found that SATB1 directly represses expression of the pro-senescence factor, p21, in dopaminergic neurons. Our data implicate senescence of dopamine neurons as a contributing factor to the pathology of Parkinson’s disease.

AAV.shRNA-mediated downregulation of ROCK2 attenuates degeneration of dopaminergic neurons in toxin-induced models of Parkinson's disease in vitro and in vivo

2015 ◽  
Vol 73 ◽  
pp. 150-162 ◽  
Author(s):  
Kim-Ann Saal ◽  
Jan C. Koch ◽  
Lars Tatenhorst ◽  
Éva M. Szegő ◽  
Vinicius Toledo Ribas ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons

scholarly journals STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease

2015 ◽  
Vol 112 (4) ◽  
pp. 1202-1207 ◽  
Author(s):  
Pradeep K. Kurup ◽  
Jian Xu ◽  
Rita Alexandra Videira ◽  
Chimezie Ononenyi ◽  
Graça Baltazar ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Tyrosine Phosphatase ◽  
Dopaminergic Neurons ◽  
Tyrosine Phosphatase ◽  
E3 Ligase ◽  
Substantia Nigra Pars Compacta ◽  
Rat Striatum ◽  
Protein Tyrosine ◽  
Cellular Models

Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The loss of SNc dopaminergic neurons affects the plasticity of striatal neurons and leads to significant motor and cognitive disabilities during the progression of the disease. PARK2 encodes for the E3 ubiquitin ligase parkin and is implicated in genetic and sporadic PD. Mutations in PARK2 are a major contributing factor in the early onset of autosomal-recessive juvenile parkinsonism (AR-JP), although the mechanisms by which a disruption in parkin function contributes to the pathophysiology of PD remain unclear. Here we demonstrate that parkin is an E3 ligase for STEP61 (striatal-enriched protein tyrosine phosphatase), a protein tyrosine phosphatase implicated in several neuropsychiatric disorders. In cellular models, parkin ubiquitinates STEP61 and thereby regulates its level through the proteasome system, whereas clinically relevant parkin mutants fail to do so. STEP61 protein levels are elevated on acute down-regulation of parkin or in PARK2 KO rat striatum. Relevant to PD, STEP61 accumulates in the striatum of human sporadic PD and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice. The increase in STEP61 is associated with a decrease in the phosphorylation of its substrate ERK1/2 and the downstream target of ERK1/2, pCREB [phospho-CREB (cAMP response element-binding protein)]. These results indicate that STEP61 is a novel substrate of parkin, although further studies are necessary to determine whether elevated STEP61 levels directly contribute to the pathophysiology of PD.

scholarly journals Postmortem studies in Parkinson's disease

2004 ◽  
Vol 6 (3) ◽  
pp. 281-293 ◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gold Standard ◽  
Dopaminergic Neurons ◽  
Nigrostriatal System ◽  
Regional Vulnerability ◽  
Environmental Agents ◽  
Postmortem Studies

No animal model to date perfectly replicates Parkinson's disease (PD) etiopathogenesis, and the anatomical organization of the nigrostriatal system differs considerably between species. Human postmortem material therefore remains the gold standard for both formulating hypotheses for subsequent testing in in vitro and in vivo PD models and verifying hypotheses derived from experimental PD models with regard to their validity in the human disease. This article focuses on recent and relevant fields in which human postmortem work has generated significant impact in our understanding of PD. These fields include Lewy body formation, regional vulnerability of dopaminergic neurons, oxidative/nitrative cellular stress, inflammation, apoptosis, infectious and environmental agents, and nondopaminergic lesions.

Polyphenols and Stem Cells for Neuroregeneration in Parkinson’s Disease and Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 27 ◽  
Author(s):  
Shweta Goyal ◽  
Brashket Seth ◽  
Rajnish Kumar Chaturvedi
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Stem Cell ◽  
Motor Neurons ◽  
Dopaminergic Neurons ◽  
Dietary Polyphenols ◽  
Lateral Sclerosis

: Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS) are neurological disorders, pathologically characterized by chronic degeneration of dopaminergic neurons and motor neurons respectively. There is still no cure or effective treatment against the disease progression and most of the treatments are symptomatic. The present review offers an overview of the different factors involved in the pathogenesis of these diseases. Subsequently, we focused on the recent advanced studies of dietary polyphenols and stem cell therapies, which have made it possible to slow down the progression of neurodegeneration. To date, stem cells and different polyphenols have been used for the directional induction of neural stem cells into dopaminergic neurons and motor neurons. We have also discussed their involvement in the modulation of different signal transduction pathways and growth factor levels in various in vivo and in vitro studies. Likewise stem cells, polyphenols also exhibit the potential of neuroprotection by their anti-apoptotic, anti-inflammatory, anti-oxidant properties regulating the growth factors levels and molecular signaling events. Overall this review provides a detailed insight into recent strategies that promise the use of polyphenol with stem cell therapy for the possible treatment of PD and ALS.

scholarly journals Protective Mechanisms of Flavonoids in Parkinson’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Kasthuri Bai Magalingam ◽  
Ammu Kutty Radhakrishnan ◽  
Nagaraja Haleagrahara
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Movement Disorder ◽  
Dopaminergic Neurons ◽  
Target Therapy ◽  
Cellular Damage ◽  
Substantia Nigra Pars Compacta ◽  
Protective Mechanisms

Parkinson’s disease is a chronic, debilitating neurodegenerative movement disorder characterized by progressive degeneration of dopaminergic neurons in thesubstantia nigra pars compactaregion in human midbrain. To date, oxidative stress is the well accepted concept in the etiology and progression of Parkinson’s disease. Hence, the therapeutic agent is targeted against suppressing and alleviating the oxidative stress-induced cellular damage. Within the past decades, an explosion of research discoveries has reported on the protective mechanisms of flavonoids, which are plant-based polyphenols, in the treatment of neurodegenerative disease using bothin vitroandin vivomodels. In this paper, we have reviewed the literature on the neuroprotective mechanisms of flavonoids in protecting the dopaminergic neurons hence reducing the symptoms of this movement disorder. The mechanism reviewed includes effect of flavonoids in activation of endogenous antioxidant enzymes, suppressing the lipid peroxidation, inhibition of inflammatory mediators, flavonoids as a mitochondrial target therapy, and modulation of gene expression in neuronal cells.

Sign in / Sign up

Export Citation Format

Share Document