Faculty Opinions recommendation of Individual dopaminergic neurons show raised iron levels in Parkinson disease.

2007 ◽  
Author(s):  
Allan Tobin
Keyword(s):  
Parkinson Disease ◽  
Dopaminergic Neurons

scholarly journals Fluorescent Parkin Cell-Based Assay Development for the Screening of Drugs against Parkinson Disease

2016 ◽  
Vol 22 (1) ◽  
pp. 67-76 ◽  
Author(s):  
Patricia Villacé ◽  
Rosa M. Mella ◽  
Meritxell Roura-Ferrer ◽  
María Valcárcel ◽  
Clarisa Salado ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Dopaminergic Neurons ◽  
Motor Impairment ◽  
Initial Response ◽  
Disease Type ◽  
New Drugs ◽  
Biological Processes ◽  
Mitochondrial Localization ◽  
Lead Identification

Parkinson disease (PD) is a prevalent neurodegenerative disease characterized by selective degeneration of dopaminergic neurons in the substantia nigra, causing tremor and motor impairment. Parkin protein, whose mutants are the cause of Parkinson disease type 2 (PARK2), has been mechanistically linked to the regulation of apoptosis and the turnover of damaged mitochondria. Several studies have implicated aberrant mitochondria as a key contributor to the development of PD. In the attempt to discover new drugs, high-content cell-based assays are becoming more important to mimic the nature of biological processes and their diversifications in diseases and will be essential for lead identification and the optimization of therapeutic candidates. We have developed a novel fluorescence cell-based assay for high-content screening to find compounds that can promote the mitochondrial localization of Parkin without severe mitochondrial damage induction. In this work, this model was used to screen a library of 1280 compounds. After the screening campaign, the positive compounds were chosen for further testing, based on the strength of the initial response and lack of cytotoxicity. These results indicated that this Parkin cell-based assay is a robust (Z′ > 0.5) and valid strategy to test potential candidates for preclinical studies.

scholarly journals Nuclear translocation of NF- B is increased in dopaminergic neurons of patients with Parkinson disease

1997 ◽  
Vol 94 (14) ◽  
pp. 7531-7536 ◽  
Author(s):  
S. Hunot ◽  
B. Brugg ◽  
D. Ricard ◽  
P. P. Michel ◽  
M.-P. Muriel ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Dopaminergic Neurons ◽  
Nuclear Translocation

Aplp1 and the Aplp1-Lag3 Complex facilitates transmission of pathologic alpha-synuclein

2021 ◽  
Author(s):  
Xiaobo Mao ◽  
Hao Gu ◽  
Donghoon Kim ◽  
Yasuyoshi Kimura ◽  
Ning Wang ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Molecular Mechanism ◽  
Amyloid Beta ◽  
Dopaminergic Neurons ◽  
Lymphocyte Activation ◽  
Alpha Synuclein ◽  
Therapeutic Strategies ◽  
Behavioral Deficits ◽  
Lymphocyte Activation Gene

Pathologic alpha-synuclein (alpha-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid beta precursor-like protein 1 (Aplp1) forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic alpha-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by alpha-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of alpha-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by alpha-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for alpha-syn PFF induced pathology advances our understanding of the molecular mechanism of cell-to-cell transmission of pathologic alpha-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson disease and related alpha-synucleinopathies.

Hypokinetic Movement Disorders: Parkinson Disease

2021 ◽  
pp. 576-582
Author(s):  
Sarah M. Tisel ◽  
Bryan T. Klassen
Keyword(s):  
Cell Death ◽  
Substantia Nigra ◽  
Parkinson Disease ◽  
Movement Disorder ◽  
Movement Disorders ◽  
Dopaminergic Neurons ◽  
Microscopic Level ◽  
Rest Tremor ◽  
Macroscopic Level ◽  
Progressive Degeneration

Parkinson disease (PD) is the classic hypokinetic movement disorder and one of the most common and widely recognized neurodegenerative conditions. PD is distinct from parkinsonism, a term that refers to a syndrome of rest tremor, bradykinesia, rigidity, and postural instability. The mechanism behind the progressive degeneration and cell death that result in PD is not precisely understood. Substantia nigra depigmentation occurs on a macroscopic level and loss of dopaminergic neurons and gliosis on a microscopic level.

scholarly journals Earliest Mechanisms of Dopaminergic Neurons Sufferance in a Novel Slow Progressing Ex Vivo Model of Parkinson Disease in Rat Organotypic Cultures of Substantia Nigra

2019 ◽  
Vol 20 (9) ◽  
pp. 2224 ◽  
Author(s):  
Matteo Dal Ben ◽  
Rosario Bongiovanni ◽  
Simone Tuniz ◽  
Emanuela Fioriti ◽  
Claudio Tiribelli ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Parkinson Disease ◽  
Dopaminergic Neurons ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Ex Vivo Model ◽  
Redox Imbalance ◽  
Clinical Phase ◽  
Protein Clearance ◽  
Persistent Inflammation

The current treatments of Parkinson disease (PD) are ineffective mainly due to the poor understanding of the early events causing the decline of dopaminergic neurons (DOPAn). To overcome this problem, slow progressively degenerating models of PD allowing the study of the pre-clinical phase are crucial. We recreated in a short ex vivo time scale (96 h) all the features of human PD (needing dozens of years) by challenging organotypic culture of rat substantia nigra with low doses of rotenone. Thus, taking advantage of the existent knowledge, the model was used to perform a time-dependent comparative study of the principal possible causative molecular mechanisms undergoing DOPAn demise. Alteration in the redox state and inflammation started at 3 h, preceding the reduction in DOPAn number (pre-diagnosis phase). The number of DOPAn declined to levels compatible with diagnosis only at 12 h. The decline was accompanied by a persistent inflammation and redox imbalance. Significant microglia activation, apoptosis, a reduction in dopamine vesicle transporters, and the ubiquitination of misfolded protein clearance pathways were late (96 h, consequential) events. The work suggests inflammation and redox imbalance as simultaneous early mechanisms undergoing DOPAn sufferance, to be targeted for a causative treatment aimed to stop/delay PD.

scholarly journals Phosphodiesterase 7 Inhibition Preserves Dopaminergic Neurons in Cellular and Rodent Models of Parkinson Disease

PLoS ONE ◽  
2011 ◽  
Vol 6 (2) ◽  
pp. e17240 ◽  
Author(s):  
Jose A. Morales-Garcia ◽  
Miriam Redondo ◽  
Sandra Alonso-Gil ◽  
Carmen Gil ◽  
Concepción Perez ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Dopaminergic Neurons ◽  
Rodent Models

Early transplantation of an encapsulated glial cell line—derived neurotrophic factor—producing cell demonstrating strong neuroprotective effects in a rat model of Parkinson disease

2005 ◽  
Vol 102 (1) ◽  
pp. 80-89 ◽  
Author(s):  
Takao Yasuhara ◽  
Tetsuro Shingo ◽  
Kenichiro Muraoka ◽  
Kazuki Kobayashi ◽  
Akira Takeuchi ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Cell Line ◽  
Glial Cell ◽  
Rat Model ◽  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Neuroprotective Effects ◽  
Content Type ◽  
Glial Proliferation ◽  
Fine Print

Object. Glial cell line—derived neurotrophic factor (GDNF) has been shown to confer neuroprotective effects on dopaminergic neurons. The authors investigated the effects of GDNF on 6-hydroxydopamine (6-OHDA)—treated dopaminergic neurons in vitro and in vivo. Methods. First, the authors examined how 1, 10, or 100 ng/ml of GDNF, administered to cells 24 hours before, simultaneously with, or 2 or 4 hours after 6-OHDA was added, affected dopaminergic neurons. In a primary culture of E14 murine ventral mesencephalic neurons, earlier treatment with the higher dosage of GDNF suppressed 6-OHDA—induced loss of dopaminergic neurons better than later treatment. Next, the authors examined whether continuous infusion of GDNF at earlier time points would demonstrate a greater neuroprotective effect in a rat model of Parkinson disease (PD). They established a human GDNF-secreting cell line, called BHK-GDNF, and encapsulated the cells into hollow fibers. The encapsulated cells were unilaterally implanted into the striatum of adult rats 1 week before; simultaneously with; or 1, 2, or 4 weeks after 6-OHDA was given to induce lesions of the same striatum. With the earlier transplantation of a BHK-GDNF capsule, there was a significant reduction in the number of amphetamine-induced rotations displayed by the animals. Rats that had received earlier implantation of BHK-GDNF capsules displayed more tyrosine hydroxylase—positive neurons in the substantia nigra pars compacta and a tendency for glial proliferation in the striatum. Conclusions. These neuroprotective effects may be related to glial proliferation and signaling via the GDNF receptor α1. The results of this study support a role for this grafting technique in the treatment of PD.

scholarly journals Bax-inhibitor-1knockdown phenotypes are suppressed byBuffyand exacerbate degeneration in aDrosophilamodel of Parkinson disease

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e2974 ◽  
Author(s):  
P. Githure M’Angale ◽  
Brian E. Staveley
Keyword(s):  
Parkinson Disease ◽  
Dopaminergic Neurons ◽  
Compound Eye ◽  
Neuronal Degeneration ◽  
Transmembrane Protein ◽  
Control Line ◽  
Altered Expression ◽  
Biometric Analysis ◽  
Climbing Ability ◽  
Locomotor Ability

BackgroundBax inhibitor-1 (BI-1) is an evolutionarily conserved cytoprotective transmembrane protein that acts as a suppressor ofBax-induced apoptosis by regulation of endoplasmic reticulum stress-induced cell death. We knocked downBI-1in the sensitivedopa decarboxylase(Ddc) expressing neurons ofDrosophila melanogasterto investigate its neuroprotective functions. We additionally sought to rescue theBI-1-induced phenotypes by co-expression with the pro-survivalBuffyand determined the effect ofBI-1knockdown on the neurodegenerative α-synuclein-induced Parkinson disease (PD) model.MethodsWe used organismal assays to assess longevity of the flies to determine the effect of the altered expression ofBI-1in theDdc-Gal4-expressing neurons by employing two RNAi transgenic fly lines. We measured the locomotor ability of these RNAi lines by computing the climbing indices of the climbing ability and compared them to a control line that expresses thelacZtransgene. Finally, we performed biometric analysis of the developing eye, where we counted the number of ommatidia and calculated the area of ommatidial disruption.ResultsThe knockdown ofBI-1in these neurons was achieved under the direction of theDdc-Gal4transgene and resulted in shortened lifespan and precocious loss of locomotor ability. The co-expression ofBuffy, the Drosophila anti-apoptotic Bcl-2 homologue, withBI-1-RNAiresulted in suppression of the reduced lifespan and impaired climbing ability. Expression of human α-synucleinin Drosophila dopaminergic neurons results in neuronal degeneration, accompanied by the age-dependent loss in climbing ability. We exploited this neurotoxic system to investigate possible BI-1 neuroprotective function. The co-expression of α-synucleinwithBI-1-RNAiresults in a slight decrease in lifespan coupled with an impairment in climbing ability. In supportive experiments, we employed the neuron-rich Drosophila compound eye to investigate subtle phenotypes that result from altered gene expression. The knockdown ofBI-1in the Drosophila developing eye under the direction of theGMR-Gal4transgene results in reduced ommatidia number and increased disruption of the ommatidial array. Similarly, the co-expression ofBI-1-RNAiwithBuffyresults in the suppression of the eye phenotypes. The expression of α-synucleinalong with the knockdown ofBI-1resulted in reduction of ommatidia number and more disruption of the ommatidial array.ConclusionKnockdown ofBI-1in the dopaminergic neurons of Drosophila results in a shortened lifespan and premature loss in climbing ability, phenotypes that appear to be strongly associated with models of PD in Drosophila, and which are suppressed upon overexpression ofBuffyand worsened by co-expression with α-synuclein. This suggests thatBI-1is neuroprotective and its knockdown can be counteracted by the overexpression of the pro-survivalBcl-2homologue.

scholarly journals ­Bcl-2 homologue debcl enhances α-synuclein-induced phenotypes in Drosophila

2016 ◽  
Author(s):  
Peter G M'Angale ◽  
Brian E Staveley
Keyword(s):  
Parkinson Disease ◽  
Dopaminergic Neurons ◽  
Neuronal Degeneration ◽  
Altered Expression ◽  
Drosophila Model ◽  
Age Dependent ◽  
Climbing Ability ◽  
The Common ◽  
Locomotor Ability

Background Parkinson disease (PD) is a debilitating movement disorder that afflicts 1 to 2% of the population over 50 years of age. The common hallmark for both sporadic and familial forms of PD is mitochondrial dysfunction. Mammals have at least twenty proapoptotic and antiapoptotic Bcl-2 family members, in contrast, only two Bcl-2 family genes have been identified in Drosophila melanogaster, the proapoptotic mitochondrial localized debcl and the antiapoptotic Buffy. The expression of α-synuclein, the first gene identified to contribute to inherited forms of PD, in the dopaminergic neurons (DA) of flies has provided a robust and well-studied Drosophila model of PD complete with the loss of neurons and accompanying motor defects. The altered expression of debcl in the DA neurons and neuron-rich eye and along with the expression of α-synuclein offers an opportunity to highlight the role of debcl in mitochondrial-dependent neuronal degeneration and death. Results The directed overexpression of debcl using the Ddc-Gal4 transgene in the dopaminergic neurons of Drosophila resulted in flies with severely decreased survival and a premature age-dependent loss in climbing ability. The inhibition of debcl resulted in enhanced survival and improved climbing ability whereas the overexpression of debcl in the α-synuclein-induced Drosophila model of PD resulted in more severe phenotypes. In addition, the co-expression of debcl along with Buffy partially counteracts the debcl-induced phenotypes, to improve the lifespan and the associated loss of locomotor ability observed. In complementary experiments, the overexpression of debcl along with the expression of α-synuclein in the eye, enhanced the eye ablation that results from the overexpression of debcl. The co-expression of Buffy along with debcl overexpression results in the rescue of the moderate developmental eye defects. The co-expression of Buffy along with inhibition of debcl partially restores the eye to a roughened eye phenotype. Discussion The overexpression of debcl in DA neurons produces flies with shortened lifespan and impaired locomotor ability, phenotypes that are strongly associated with models of PD in Drosophila. The co-expression of debcl along with α-synuclein enhanced the Parkinson disease-like phenotypes. The co-expression of debcl along with Buffy suppresses these phenotypes. Complementary experiments in the Drosophila eye show similar trends during development. Taken all together these results suggest a role for debcl in neurodegenerative disorders.

scholarly journals Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy

2021 ◽  
Vol 5 (2) ◽  
pp. e202101287
Author(s):  
Emma V Rusilowicz-Jones ◽  
Francesco G Barone ◽  
Fernanda Martins Lopes ◽  
Elezabeth Stephen ◽  
Heather Mortiboys ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Dopaminergic Neurons ◽  
Enzymatic Assay ◽  
Pharmacological Intervention ◽  
Loss Of Function ◽  
Biological Characterization ◽  
Mitochondrial Depolarization ◽  
Synthetic Molecule

The deubiquitylase USP30 is an actionable target considered for treatment of conditions associated with defects in the PINK1-PRKN pathway leading to mitophagy. We provide a detailed cell biological characterization of a benzosulphonamide molecule, compound 39, that has previously been reported to inhibit USP30 in an in vitro enzymatic assay. The current compound offers increased selectivity over previously described inhibitors. It enhances mitophagy and generates a signature response for USP30 inhibition after mitochondrial depolarization. This includes enhancement of TOMM20 and SYNJ2BP ubiquitylation and phosphoubiquitin accumulation, alongside increased mitophagy. In dopaminergic neurons, generated from Parkinson disease patients carrying loss of function PRKN mutations, compound 39 could significantly restore mitophagy to a level approaching control values. USP30 is located on both mitochondria and peroxisomes and has also been linked to the PINK1-independent pexophagy pathway. Using a fluorescence reporter of pexophagy expressed in U2OS cells, we observe increased pexophagy upon application of compound 39 that recapitulates the previously described effect for USP30 depletion. This provides the first pharmacological intervention with a synthetic molecule to enhance peroxisome turnover.

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