scholarly journals Copper and Copper Proteins in Parkinson’s Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Sergio Montes ◽  
Susana Rivera-Mancia ◽  
Araceli Diaz-Ruiz ◽  
Luis Tristan-Lopez ◽  
Camilo Rios
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Copper Binding ◽  
Copper Proteins ◽  
Limited Information ◽  
Copper Chelation

Copper is a transition metal that has been linked to pathological and beneficial effects in neurodegenerative diseases. In Parkinson’s disease, free copper is related to increased oxidative stress, alpha-synuclein oligomerization, and Lewy body formation. Decreased copper along with increased iron has been found insubstantia nigraand caudate nucleus of Parkinson’s disease patients. Copper influences iron content in the brain through ferroxidase ceruloplasmin activity; therefore decreased protein-bound copper in brain may enhance iron accumulation and the associated oxidative stress. The function of other copper-binding proteins such as Cu/Zn-SOD and metallothioneins is also beneficial to prevent neurodegeneration. Copper may regulate neurotransmission since it is released after neuronal stimulus and the metal is able to modulate the function of NMDA and GABA A receptors. Some of the proteins involved in copper transport are the transporters CTR1, ATP7A, and ATP7B and the chaperone ATOX1. There is limited information about the role of those biomolecules in the pathophysiology of Parkinson’s disease; for instance, it is known that CTR1 is decreased insubstantia nigra pars compactain Parkinson’s disease and that a mutation in ATP7B could be associated with Parkinson’s disease. Regarding copper-related therapies, copper supplementation can represent a plausible alternative, while copper chelation may even aggravate the pathology.

scholarly journals Gender biased neuroprotective effect of Transferrin Receptor 2 deletion in multiple models of Parkinson’s disease

2020 ◽  
Author(s):  
Chiara Milanese ◽  
Sylvia Gabriels ◽  
Sander Barnhoorn ◽  
Silvia Cerri ◽  
Ayse Ulusoy ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Iron Overload ◽  
Transferrin Receptor ◽  
Dopaminergic Neurons ◽  
Iron Homeostasis ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Transferrin Receptor 2

AbstractAlterations in the metabolism of iron and its accumulation in the substantia nigra pars compacta accompany the pathogenesis of Parkinson’s disease (PD). Changes in iron homeostasis also occur during aging, which constitutes a PD major risk factor. As such, mitigation of iron overload via chelation strategies has been considered a plausible disease modifying approach. Iron chelation, however, is imperfect because of general undesired side effects and lack of specificity; more effective approaches would rely on targeting distinctive pathways responsible for iron overload in brain regions relevant to PD and, in particular, the substantia nigra. We have previously demonstrated that the Transferrin/Transferrin Receptor 2 (TfR2) iron import mechanism functions in nigral dopaminergic neurons, is perturbed in PD models and patients, and therefore constitutes a potential therapeutic target to halt iron accumulation. To validate this hypothesis, we generated mice with targeted deletion of TfR2 in dopaminergic neurons. In these animals, we modeled PD with multiple approaches, based either on neurotoxin exposure or alpha-synuclein proteotoxic mechanisms. We found that TfR2 deletion can provide neuroprotection against dopaminergic degeneration, and against PD- and aging-related iron overload. The effects, however, were significantly more pronounced in females rather than in males. Our data indicate that the TfR2 iron import pathway represents an amenable strategy to hamper PD progression. Data also suggest, however, that therapeutic strategies targeting TfR2 should consider a potential sexual dimorphism in neuroprotective response.

Lemon grass extract alleviates oxidative stress and delayed the loss of climbing ability in transgenic Drosophila model of Parkinson’s disease

2021 ◽  
Vol 18 ◽  
Author(s):  
Yasir Hasan Siddique ◽  
Falaq Naz ◽  
Mantasha I. ◽  
M. Shahid
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Positive Interaction ◽  
Lemon Grass ◽  
Drosophila Model ◽  
Climbing Ability ◽  
Transgenic Drosophila

Background: Parkinson’s Disease (PD) is characterized by the aggregation of α-synuclein, formation of Lewy bodies and the selective loss of dopaminergic neurons of mesencephalic substantia nigra pars compacta (SNC) with the debilitating motor symptoms. Introduction: The available treatment for PD provides symptomatic relief with no control on the progression of the disease. The treatment is also associated with several side effects. As the neurodegeneration in PD is also associated with the oxidative stress, antioxidants from plants could play an important role in reducing the PD symptoms. With this aim we decided to study the effect of Lemon grass extract (LGE) on the transgenic Drosophila model of PD expressing human alpha synuclein in the neurons. Methods: The PD flies allowed were allowed to feed on different doses of LGE established in diet for 24 days and then assayed for climbing ability and oxidative stress markers. The molecular docking study was also performed for citral (the component of the extract) and human α-synuclein. Results and discussion: A dose dependent significant improvement in the climbing ability and reduction in oxidative stress was observed in the PD flies exposed to LGE. In our earlier study on LGE, citral was found to be the main component of the extract by GC-MS analysis. The docking results also support the positive interaction between citral and human α-synuclein. Conclusion: The results suggests that LGE is potemnt in reducing the PD symptoms being mimicked in transgenic Drosophila.

scholarly journals A Computational Model of Levodopa-Induced Toxicity in Substantia Nigra Pars Compacta in Parkinson’s Disease

2020 ◽  
Author(s):  
Vignayanandam Ravindernath Muddapu ◽  
Karthik Vijayakumar ◽  
Keerthiga Ramakrishnan ◽  
V Srinivasa Chakravarthy
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Computational Model ◽  
Energy Demand ◽  
High Energy ◽  
Substantia Nigra Pars Compacta ◽  
Striatal Neurons ◽  
Energy Deficiency

ABSTRACTBackgroundParkinson’s disease (PD) is caused by the progressive loss of dopaminergic cells in substantia nigra pars compacta (SNc). The root cause of this cell loss in PD is still not decisively elucidated. A recent line of thinking traces the cause of PD neurodegeneration to metabolic deficiency. Due to exceptionally high energy demand, SNc neurons exhibit a higher basal metabolic rate and higher oxygen consumption rate, which results in oxidative stress. Recently, we have suggested that the excitotoxic loss of SNc cells might be due to energy deficiency occurring at different levels of neural hierarchy. Levodopa (LDOPA), a precursor of dopamine, which is used as a symptom-relieving treatment for PD, leads to outcomes that are both positive and negative. Several researchers suggested that LDOPA might be harmful to SNc cells due to oxidative stress. The role of LDOPA in the course of PD pathogenesis is still debatable.New MethodWe hypothesize that energy deficiency can lead to LDOPA-induced toxicity (LIT) in two ways: by promoting dopamine-induced oxidative stress and by exacerbating excitotoxicity in SNc. We present a multiscale computational model of SNc-striatum system, which will help us in understanding the mechanism behind neurodegeneration postulated above and provides insights for developing disease-modifying therapeutics.ResultsIt was observed that SNc terminals are more vulnerable to energy deficiency than SNc somas. During LDOPA therapy, it was observed that higher LDOPA dosage results in increased loss of somas and terminals in SNc. It was also observed that co-administration of LDOPA and glutathione (antioxidant) evades LDOPA-induced toxicity in SNc neurons.Comparison with Existing MethodsOur proposed multiscale model of SNc-striatum system is first of its kind, where SNc neuron was modelled at biophysical level, and striatal neurons were modelled at spiking level.ConclusionsWe show that our proposed model was able to capture LDOPA-induced toxicity in SNc, caused by energy deficiency.

scholarly journals Cholinergic Receptor Modulation as a Target for Preventing Dementia in Parkinson’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Alexandre Iarkov ◽  
Cristhian Mendoza ◽  
Valentina Echeverria
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Cholinergic System ◽  
Acetylcholine Receptors ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Motor Functions ◽  
Receptor Modulation

Parkinson’s disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) in the midbrain resulting in progressive impairment in cognitive and motor abilities. The physiological and molecular mechanisms triggering dopaminergic neuronal loss are not entirely defined. PD occurrence is associated with various genetic and environmental factors causing inflammation and mitochondrial dysfunction in the brain, leading to oxidative stress, proteinopathy, and reduced viability of dopaminergic neurons. Oxidative stress affects the conformation and function of ions, proteins, and lipids, provoking mitochondrial DNA (mtDNA) mutation and dysfunction. The disruption of protein homeostasis induces the aggregation of alpha-synuclein (α-SYN) and parkin and a deficit in proteasome degradation. Also, oxidative stress affects dopamine release by activating ATP-sensitive potassium channels. The cholinergic system is essential in modulating the striatal cells regulating cognitive and motor functions. Several muscarinic acetylcholine receptors (mAChR) and nicotinic acetylcholine receptors (nAChRs) are expressed in the striatum. The nAChRs signaling reduces neuroinflammation and facilitates neuronal survival, neurotransmitter release, and synaptic plasticity. Since there is a deficit in the nAChRs in PD, inhibiting nAChRs loss in the striatum may help prevent dopaminergic neurons loss in the striatum and its pathological consequences. The nAChRs can also stimulate other brain cells supporting cognitive and motor functions. This review discusses the cholinergic system as a therapeutic target of cotinine to prevent cognitive symptoms and transition to dementia in PD.

scholarly journals Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet

2010 ◽  
Vol 299 (4) ◽  
pp. R1082-R1090 ◽  
Author(s):  
Jill K. Morris ◽  
Gregory L. Bomhoff ◽  
John A. Stanford ◽  
Paige C. Geiger
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Locomotor Activity ◽  
Substantia Nigra ◽  
High Fat Diet ◽  
Model Assessment ◽  
High Fat

Despite numerous clinical studies supporting a link between type 2 diabetes (T2D) and Parkinson's disease (PD), the clinical literature remains equivocal. We, therefore, sought to address the relationship between insulin resistance and nigrostriatal dopamine (DA) in a preclinical animal model. High-fat feeding in rodents is an established model of insulin resistance, characterized by increased adiposity, systemic oxidative stress, and hyperglycemia. We subjected rats to a normal chow or high-fat diet for 5 wk before infusing 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Our goal was to determine whether a high-fat diet and the resulting peripheral insulin resistance would exacerbate 6-OHDA-induced nigrostriatal DA depletion. Prior to 6-OHDA infusion, animals on the high-fat diet exhibited greater body weight, increased adiposity, and impaired glucose tolerance. Two weeks after 6-OHDA, locomotor activity was tested, and brain and muscle tissue was harvested. Locomotor activity did not differ between the groups nor did cholesterol levels or measures of muscle atrophy. High-fat-fed animals exhibited higher homeostatic model assessment of insulin resistance (HOMA-IR) values and attenuated insulin-stimulated glucose uptake in fast-twitch muscle, indicating decreased insulin sensitivity. Animals in the high-fat group also exhibited greater DA depletion in the substantia nigra and the striatum, which correlated with HOMA-IR and adiposity. Decreased phosphorylation of HSP27 and degradation of IκBα in the substantia nigra indicate increased tissue oxidative stress. These findings support the hypothesis that a diet high in fat and the resulting insulin resistance may lower the threshold for developing PD, at least following DA-specific toxin exposure.

scholarly journals Alpha-Synuclein Oligomers Interact with Metal Ions to Induce Oxidative Stress and Neuronal Death in Parkinson's Disease

2016 ◽  
Vol 24 (7) ◽  
pp. 376-391 ◽  
Author(s):  
Emma Deas ◽  
Nunilo Cremades ◽  
Plamena R. Angelova ◽  
Marthe H.R. Ludtmann ◽  
Zhi Yao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Metal Ions ◽  
Neuronal Death ◽  
Alpha Synuclein

scholarly journals Metabolomics Fingerprint Induced by the Intranigral Inoculation of Exogenous Human Alpha-Synuclein Oligomers in a Rat Model of Parkinson’s Disease

2020 ◽  
Vol 21 (18) ◽  
pp. 6745
Author(s):  
Federica Murgia ◽  
Luigi Atzori ◽  
Ezio Carboni ◽  
Maria Laura Santoru ◽  
Aran Hendren ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dehydroascorbic Acid ◽  
Alpha Synuclein ◽  
Mass Spectrometry Analysis ◽  
Substantia Nigra Pars Compacta ◽  
Gas Chromatography Mass Spectrometry ◽  
Serum Samples ◽  
Spectrometry Analysis ◽  
Metabolite Content

Parkinson’s disease (PD) is considered a synucleinopathy because of the intraneuronal accumulation of aggregated α-synuclein (αSyn). Recent evidence points to soluble αSyn-oligomers (αSynO) as the main cytotoxic species responsible for cell death. Given the pivotal role of αSyn in PD, αSyn-based models are crucial for the investigation of toxic mechanisms and the identification of new therapeutic targets in PD. By using a metabolomics approach, we evaluated the metabolic profile of brain and serum samples of rats infused unilaterally with preformed human αSynOs (HαSynOs), or vehicle, into the substantia nigra pars compacta (SNpc). Three months postinfusion, the striatum was dissected for striatal dopamine (DA) measurements via High Pressure Liquid Chromatography (HPLC) analysis and mesencephalon and serum samples were collected for the evaluation of metabolite content via gas chromatography mass spectrometry analysis. Multivariate, univariate and correlation statistics were applied. A 40% decrease of DA content was measured in the HαSynO-infused striatum as compared to the contralateral and the vehicle-infused striata. Decreased levels of dehydroascorbic acid, myo-inositol, and glycine, and increased levels of threonine, were found in the mesencephalon, while increased contents of fructose and mannose, and a decrease in glycine and urea, were found in the serum of HαSynO-infused rats. The significant correlation between DA and metabolite content indicated that metabolic variations reflected the nigrostriatal degeneration. Collectively, the metabolomic fingerprint of HαSynO-infused rats points to an increase of oxidative stress markers, in line with PD neuropathology, and provides hints for potential biomarkers of PD.

scholarly journals Effect of Curcumin on Protein Damage Induced by Rotenone in Dopaminergic PC12 Cells

2020 ◽  
Vol 21 (8) ◽  
pp. 2761 ◽  
Author(s):  
Sandra Buratta ◽  
Elisabetta Chiaradia ◽  
Alessia Tognoloni ◽  
Angela Gambelunghe ◽  
Consuelo Meschini ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Pc12 Cells ◽  
Cell Function ◽  
Neurodegenerative Disorder ◽  
Cell Model ◽  
Antioxidant Properties ◽  
Protein Damage ◽  
Substantia Nigra Pars Compacta

Oxidative stress is considered to be a key factor of the pathogenesis of Parkinson’s disease, a multifactorial neurodegenerative disorder characterized by reduced dopaminergic neurons in the substantia nigra pars compacta and accumulated protein aggregates. Rotenone is a worldwide-used pesticide that induces the most common features of Parkinson’s by direct inhibition of the mitochondrial complex I. Rotenone-induced Parkinson’s models, as well as brain tissues from Parkinson’s patients, are characterized by the presence of both lipid peroxidation and protein oxidation markers resulting from the increased level of free radical species. Oxidation introduces several modifications in protein structure, including carbonylation and nitrotyrosine formation, which severely compromise cell function. Due to the link existing between oxidative stress and Parkinson’s disease, antioxidant molecules could represent possible therapeutic tools for this disease. In this study, we evaluated the effect of curcumin, a natural compound known for its antioxidant properties, in dopaminergic PC12 cells treated with rotenone, a cell model of Parkinsonism. Our results demonstrate that the treatment of PC12 cells with rotenone causes severe protein damage, with formation of both carbonylated and nitrotyrosine-derived proteins, whereas curcumin (10 µM) co-exposure exerts protective effects by reducing the levels of oxidized proteins. Curcumin also promotes proteasome activation, abolishing the inhibitory effect exerted by rotenone on this degradative system.

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