scholarly journals Co-Expression of Nogo-A in Dopaminergic Neurons of the Human Substantia Nigra Pars Compacta Is Reduced in Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3368
Author(s):  
Gian-Carlo Eyer ◽  
Stefano Di Santo ◽  
Ekkehard Hewer ◽  
Lukas Andereggen ◽  
Stefanie Seiler ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Collaborative Effort ◽  
Tissue Micro Array ◽  
Progressive Loss ◽  
Micro Array

Parkinson’s disease is mainly characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Together with the small number, the high vulnerability of the dopaminergic neurons is a major pathogenic culprit of Parkinson’s disease. Our previous findings of a higher survival of dopaminergic neurons in the substantia nigra co-expressing Nogo-A in an animal model of Parkinson’s disease suggested that Nogo-A may be associated with dopaminergic neurons resilience against Parkinson’s disease neurodegeneration. In the present study, we have addressed the expression of Nogo-A in the dopaminergic neurons in the substantia nigra in postmortem specimens of diseased and non-diseased subjects of different ages. For this purpose, in a collaborative effort we developed a tissue micro array (TMA) that allows for simultaneous staining of many samples in a single run. Interestingly, and in contrast to the observations gathered during normal aging and in the animal model of Parkinson’s disease, increasing age was significantly associated with a lower co-expression of Nogo-A in nigral dopaminergic neurons of patients with Parkinson’s disease. In sum, while Nogo-A expression in dopaminergic neurons is higher with increasing age, the opposite is the case in Parkinson’s disease. These observations suggest that Nogo-A might play a substantial role in the vulnerability of dopaminergic neurons in Parkinson’s disease.

scholarly journals To be or not to be pink(1): contradictory findings in an animal model for Parkinson’s disease

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Ria de Haas ◽  
Lisa C M W Heltzel ◽  
Denise Tax ◽  
Petra van den Broek ◽  
Hilbert Steenbreker ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
In Vivo Microdialysis ◽  
Substantia Nigra Pars Compacta ◽  
Laboratory Animals ◽  
Motor Deficits

Abstract The PTEN-induced putative kinase 1 knockout rat (Pink1−/−) is marketed as an established model for Parkinson’s disease, characterized by development of motor deficits and progressive degeneration of half the dopaminergic neurons in the substantia nigra pars compacta by 8 months of age. In this study, we address our concerns about the reproducibility of the Pink1−/− rat model. We evaluated behavioural function, number of substantia nigra dopaminergic neurons and extracellular striatal dopamine concentrations by in vivo microdialysis. Strikingly, we and others failed to observe any loss of dopaminergic neurons in 8-month-old male Pink1−/− rats. To understand this variability, we compared key experimental parameters from the different studies and provide explanations for contradictory findings. Although Pink1−/− rats developed behavioural deficits, these could not be attributed to nigrostriatal degeneration as there was no loss of dopaminergic neurons in the substantia nigra and no changes in neurotransmitter levels in the striatum. To maximize the benefit of Parkinson’s disease research and limit the unnecessary use of laboratory animals, it is essential that the research community is aware of the limits of this animal model. Additional research is needed to identify reasons for inconsistency between Pink1−/− rat colonies and why degeneration in the substantia nigra is not consistent.

Parkinson's Disease

2019 ◽  
pp. 252-273 ◽  
Author(s):  
Vaibhav Walia ◽  
Ashish Gakkhar ◽  
Munish Garg
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Older Patients ◽  
Neurodegenerative Disorder ◽  
Progressive Loss ◽  
The Brain

Parkinson's disease (PD) is a neurodegenerative disorder in which a progressive loss of the dopaminergic neurons occurs. The loss of the neurons is most prominent in the substantia nigra region of the brain. The prevalence of PD is much greater among the older patients suggesting the risk of PD increases with the increase of age. The exact cause of the neurodegeneration in PD is not known. In this chapter, the authors introduce PD, demonstrate its history, pathogenesis, neurobiology, sign and symptoms, diagnosis, and pharmacotherapy.

scholarly journals Detection of Parkinson’s Disease from 3T T1 Weighted MRI Scans Using 3D Convolutional Neural Network

Diagnostics ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 402
Author(s):  
Sabyasachi Chakraborty ◽  
Satyabrata Aich ◽  
Hee-Cheol Kim
Keyword(s):  
Neural Network ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Convolutional Neural Network ◽  
Dopaminergic Neurons ◽  
Aging Population ◽  
Substantia Nigra Pars Compacta ◽  
Progressive Loss ◽  
Mri Scans ◽  
Magnetic Resonance Imaging Mri

Parkinson’s Disease is a neurodegenerative disease that affects the aging population and is caused by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). With the onset of the disease, the patients suffer from mobility disorders such as tremors, bradykinesia, impairment of posture and balance, etc., and it progressively worsens in the due course of time. Additionally, as there is an exponential growth of the aging population in the world the number of people suffering from Parkinson’s Disease is increasing and it levies a huge economic burden on governments. However, until now no therapeutic method has been discovered for completely eradicating the disease from a person’s body after it’s onset. Therefore, the early detection of Parkinson’s Disease is of paramount importance to tackle the progressive loss of dopaminergic neurons in patients to serve them with a better life. In this study, 3T T1-weighted MRI scans were acquired from the Parkinson’s Progression Markers Initiative (PPMI) database of 406 subjects from baseline visit, where 203 were healthy and 203 were suffering from Parkinson’s Disease. Following data pre-processing, a 3D convolutional neural network (CNN) architecture was developed for learning the intricate patterns in the Magnetic Resonance Imaging (MRI) scans for the detection of Parkinson’s Disease. In the end, it was observed that the developed 3D CNN model performed superiorly by completely aligning with the hypothesis of the study and plotted an overall accuracy of 95.29%, average recall of 0.943, average precision of 0.927, average specificity of 0.9430, f1-score of 0.936, and Receiver Operating Characteristic—Area Under Curve (ROC-AUC) score of 0.98 for both the classes respectively.

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.

Polyomic analyses of dopaminergic neurons isolated from human substantia nigra in Parkinson’s disease: An exploratory study.

2021 ◽  
Author(s):  
Affif ZACCARIA ◽  
Paola Antinori Malaspina ◽  
Virginie Licker ◽  
Enikö Kovari ◽  
Johannes A Lobrinus ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Protein Expression ◽  
Differential Expression ◽  
Dopaminergic Neurons ◽  
Exploratory Study ◽  
Substantia Nigra Pars Compacta ◽  
Gene And Protein Expression ◽  
And Control

Abstract Dopaminergic neurons of the substantia nigra pars compacta selectively and progressively degenerate in Parkinson’s disease. Until now, molecular analyses of dopaminergic neurons in PD have been limited to genomic and transcriptomic approaches, whereas, to the best of our knowledge, no proteomic or combined polyomic study examining the protein profile of these neurons, is currently available. In this exploratory study, we used laser microdissection to extract dopaminergic neurons from 10 human SNpc samples obtained at autopsy in Parkinson’s disease patients and control subjects. Extracted RNA and proteins were identified by RNA sequencing and nano-LC-MS/MS, respectively, and the differential expression between Parkinson’s disease and control group was assessed. Qualitative analyses confirmed that the microdissection protocol preserves the integrity of our samples and offers access to specific molecular pathways. This polyomic analysis highlighted differential expression of 52 genes and 33 proteins, including molecules of interest already known to be dysregulated in Parkinson’s disease, such as LRP2 , PNMT , CXCR4 , MAOA and CBLN1 genes, or the Aldehyde dehydrogenase 1 protein. On the other hand, despite the same samples were used for both analyses, correlation between RNA and protein expression was low, as exemplified by the CST3 gene encoding for the cystatin C protein. This is the first exploratory study analyzing both gene and protein expression of LMD-dissected neurons from substantia nigra pars compacta in Parkinson’s disease. Data are available via ProteomeXchange with identifier PXD024748 and via GEO with identifier GSE 169755.

scholarly journals Neuronal hemoglobin induces α-synuclein cleavage and loss of dopaminergic neurons

2021 ◽  
Author(s):  
Chiara Santulli ◽  
Carlotta Bon ◽  
Elena De Cecco ◽  
Marta Codrich ◽  
Joanna Narkiewicz ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Spatial Working Memory ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Major Protein ◽  
Post Translational Modification ◽  
Over Expression

Backgroud α-synuclein, a protein involved in the pathogenesis of several neurodegenerative disorders, is subjected to several post-translational modifications. Among them, C-terminal truncation seems to increase its aggregation propensity in vitro. Hemoglobin is the major protein in erythrocytes to carries oxygen and recently is found to be expressed in dopaminergic neurons and to be involved in the pathogenesis of neurodegenerative diseases such as Parkinson's disease. Methods To assess the role of hemoglobin in α-synuclein post-translational modification and in dopamine cells physiology, we over-expressed α and β-chains of Hb in iMN9D dopamine cells to evaluate its effect on α-synuclein truncation. Using an AAV9 we expressed α and β-chains of hemoglobin in dopamine neurons of Substantia Nigra pars compacta and evaluate its effect on α-synuclein post-translational modification, dopamine neurons survivals and behavioural outcome. Results The over-expression of α and β-chains of hemoglobin in iMN9D dopamine cells increased C-terminal truncation of α-synuclein when cells were treated with α-synuclein preformed fibrils. This cleavage was led at least in part by Calpain protease. Hemoglobin over-expression in Substantia Nigra pars compacta induced a similar pattern of α-synuclein truncation and a decrease in tyrosine hydroxylase expression, unveiling a decrease of dopamine neurons of about 50%. This dopamine cells loss led to a mild motor impairment and a deficit in recognition and spatial working memory. Conclusion Our study reveals a novel role for hemoglobin in α-synuclein post-translational modification and in dopamine neurons homeostasis suggesting neuronal hemoglobin is an important modifier in synucleinopathies such as Parkinson's disease.

scholarly journals MicroRNA Dysregulation in Parkinson’s Disease: A Narrative Review

2021 ◽  
Vol 15 ◽  
Author(s):  
Yong Hui Nies ◽  
Nor Haliza Mohamad Najib ◽  
Wei Ling Lim ◽  
Mohd Amir Kamaruzzaman ◽  
Mohamad Fairuz Yahaya ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Expression Profiles ◽  
Lewy Bodies ◽  
Complete Recovery ◽  
Substantia Nigra Pars Compacta ◽  
Dopamine Depletion ◽  
Gene And Protein Expression

Parkinson’s disease (PD) is a severely debilitating neurodegenerative disease, affecting the motor system, leading to resting tremor, cogwheel rigidity, bradykinesia, walking and gait difficulties, and postural instability. The severe loss of dopaminergic neurons in the substantia nigra pars compacta causes striatal dopamine deficiency and the presence of Lewy bodies indicates a pathological hallmark of PD. Although the current treatment of PD aims to preserve dopaminergic neurons or to replace dopamine depletion in the brain, it is notable that complete recovery from the disease is yet to be achieved. Given the complexity and multisystem effects of PD, the underlying mechanisms of PD pathogenesis are yet to be elucidated. The advancement of medical technologies has given some insights in understanding the mechanism and potential treatment of PD with a special interest in the role of microRNAs (miRNAs) to unravel the pathophysiology of PD. In PD patients, it was found that striatal brain tissue and dopaminergic neurons from the substantia nigra demonstrated dysregulated miRNAs expression profiles. Hence, dysregulation of miRNAs may contribute to the pathogenesis of PD through modulation of PD-associated gene and protein expression. This review will discuss recent findings on PD-associated miRNAs dysregulation, from the regulation of PD-associated genes, dopaminergic neuron survival, α-synuclein-induced inflammation and circulating miRNAs. The next section of this review also provides an update on the potential uses of miRNAs as diagnostic biomarkers and therapeutic tools for PD.

Sign in / Sign up

Export Citation Format

Share Document