scholarly journals Phenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Benedict Tanudjojo ◽  
Samiha S. Shaikh ◽  
Alexis Fenyi ◽  
Luc Bousset ◽  
Devika Agarwal ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Multiple System Atrophy ◽  
Neuronal Death ◽  
Dopaminergic Neurons ◽  
De Novo ◽  
Dependent Manner ◽  
Human Neurons ◽  
Phenotypic Manifestation ◽  
Induced Aggregation

Abstractα-Synuclein is critical in the pathogenesis of Parkinson’s disease and related disorders, yet it remains unclear how its aggregation causes degeneration of human dopaminergic neurons. In this study, we induced α-synuclein aggregation in human iPSC-derived dopaminergic neurons using fibrils generated de novo or amplified in the presence of brain homogenates from Parkinson’s disease or multiple system atrophy. Increased α-synuclein monomer levels promote seeded aggregation in a dose and time-dependent manner, which is associated with a further increase in α-synuclein gene expression. Progressive neuronal death is observed with brain-amplified fibrils and reversed by reduction of intraneuronal α-synuclein abundance. We identified 56 proteins differentially interacting with aggregates triggered by brain-amplified fibrils, including evasion of Parkinson’s disease-associated deglycase DJ-1. Knockout of DJ-1 in iPSC-derived dopaminergic neurons enhance fibril-induced aggregation and neuronal death. Taken together, our results show that the toxicity of α-synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our study demonstrates how Parkinson’s disease-associated genes influence the phenotypic manifestation of strains in human neurons.

scholarly journals Demonstration of brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson’s disease

2020 ◽  
Vol 29 (7) ◽  
pp. 1180-1191
Author(s):  
Razvan-Marius Brazdis ◽  
Julian E Alecu ◽  
Daniel Marsch ◽  
Annika Dahms ◽  
Katrin Simmnacher ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Brain Region ◽  
Neuronal Death ◽  
Dopaminergic Neurons ◽  
Control Individual ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Human Ipscs

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder characterized by protein inclusions mostly composed of aggregated forms of α-synuclein (α-Syn) and by the progressive degeneration of midbrain dopaminergic neurons (mDANs), resulting in motor symptoms. While other brain regions also undergo pathologic changes in PD, the relevance of α-Syn aggregation for the preferential loss of mDANs in PD pathology is not completely understood yet. To elucidate the mechanisms of the brain region-specific neuronal vulnerability in PD, we modeled human PD using human-induced pluripotent stem cells (iPSCs) from familial PD cases with a duplication (Dupl) of the α-Syn gene (SNCA) locus. Human iPSCs from PD Dupl patients and a control individual were differentiated into mDANs and cortical projection neurons (CPNs). SNCA dosage increase did not influence the differentiation efficiency of mDANs and CPNs. However, elevated α-Syn pathology, as revealed by enhanced α-Syn insolubility and phosphorylation, was determined in PD-derived mDANs compared with PD CPNs. PD-derived mDANs exhibited higher levels of reactive oxygen species and protein nitration levels compared with CPNs, which might underlie elevated α-Syn pathology observed in mDANs. Finally, increased neuronal death was observed in PD-derived mDANs compared to PD CPNs and to control mDANs and CPNs. Our results reveal, for the first time, a higher α-Syn pathology, oxidative stress level, and neuronal death rate in human PD mDANs compared with PD CPNs from the same patient. The finding implies the contribution of pathogenic α-Syn, probably induced by oxidative stress, to selective vulnerability of substantia nigra dopaminergic neurons in human PD.

scholarly journals Novel Tools towards Magnetic Guidance of Neurite Growth: (I) Guidance of Magnetic Nanoparticles into Neurite Extensions of Induced Human Neurons and In Vitro Functionalization with RAS Regulating Proteins

2019 ◽  
Vol 10 (3) ◽  
pp. 32 ◽  
Author(s):  
Hendrik Schöneborn ◽  
Fabian Raudzus ◽  
Emilie Secret ◽  
Nils Otten ◽  
Aude Michel ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Magnetic Nanoparticles ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Covalent Binding ◽  
Neurite Growth ◽  
Correlation Spectroscopy ◽  
Exchange Factor ◽  
Human Neurons

Parkinson’s disease (PD) is a neurodegenerative disease associated with loss or dysfunction of dopaminergic neurons located in the substantia nigra (SN), and there is no cure available. An emerging new approach for treatment is to transplant human induced dopaminergic neurons directly into the denervated striatal brain target region. Unfortunately, neurons grafted into the substantia nigra are unable to grow axons into the striatum and thus do not allow recovery of the original connectivity. Towards overcoming this general limitation in guided neuronal regeneration, we develop here magnetic nanoparticles functionalized with proteins involved in the regulation of axonal growth. We show covalent binding of constitutive active human rat sarcoma (RAS) proteins or RAS guanine nucleotide exchange factor catalytic domain of son of sevenless (SOS) by fluorescence correlation spectroscopy and multiangle light scattering as well as the characterization of exchange factor activity. Human dopaminergic neurons were differentiated from neural precursor cells and characterized by electrophysiological and immune histochemical methods. Furthermore, we demonstrate magnetic translocation of cytoplasmic γ-Fe2O3@SiO2 core-shell nanoparticles into the neurite extensions of induced human neurons. Altogether, we developed tools towards remote control of directed neurite growth in human dopaminergic neurons. These results may have relevance for future therapeutic approaches of cell replacement therapy in Parkinson’s disease.

scholarly journals ATF4 regulates neuronal death in models of Parkinson’s Disease

2019 ◽  
Author(s):  
Matthew D. Demmings ◽  
Gillian N. Petroff ◽  
Heather E. Tarnowski-Garner ◽  
Sean P. Cregan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcription Factor ◽  
Neuronal Death ◽  
Target Genes ◽  
Kinase Inhibitor ◽  
Alpha Synuclein ◽  
Dependent Manner ◽  
Dopaminergic Cell ◽  
Cellular Models

AbstractParkinson’s Disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra resulting in severe motor impairments. However, the mechanisms underlying this neuronal loss remain largely unknown. Activating Transcription Factor 4 (ATF4), a key mediator of the Integrated Stress Response (ISR), is a transcription factor that during prolonged activation can induce the expression of pro-apoptotic target genes. Oxidative stress and ER stress have been implicated in PD and these factors are known to activate the ISR. In this study, we have determined, that both PD neurotoxins (MPP+ and 6-OHDA) and α-synuclein aggregation induced by pre-formed human alpha-synuclein fibrils (PFFs) cause sustained upregulation of ATF4 expression in mouse primary cortical and mesencephalic neurons. Furthermore, we demonstrate that PD neurotoxins induce the expression of the pro-apoptotic factors Chop, Trb3 and Puma in an ATF4-dependent manner. Importantly, using neurons derived from ATF4 +/+ and ATF4 -/- mice, we demonstrate that ATF4 promotes neuronal apoptosis and dopaminergic cell loss in cellular models of PD. Finally, we demonstrate that the eIF2α kinase inhibitor C16 suppresses MPP+ and 6-OHDA induced ATF4 activation and protects against PD neurotoxin induced neuronal death. Taken together these results indicate that ATF4 is a key regulator of dopaminergic cell death induced by PD neurotoxins and pathogenic α-synuclein aggregates and highlight the ISR as a potential therapeutic target in PD.

Salsolinol, an endogenous neurotoxin, enhances platelet aggregation and thrombus formation

2008 ◽  
Vol 100 (07) ◽  
pp. 52-59 ◽  
Author(s):  
Kyung-Min Lim ◽  
Ji-Yoon Noh ◽  
Seung-Min Chung ◽  
Keunyoung Kim ◽  
Suyoung Hong ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Platelet Aggregation ◽  
Adrenergic Receptor ◽  
Thrombus Formation ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Vessel Occlusion ◽  
Occlusion Time ◽  
Induced Aggregation

SummarySalsolinol, an endogenous neurotoxin, is known to be involved in the neuropathy of Parkinson’s disease and chronic alcoholism. In these diseases, increased thrombotic events are also commonly reported, yet the mechanism underlying remains poorly understood. Here we report that salsolinol can enhance agonist-induced platelet aggregation and granular secretion, which is essential in the thrombus formation. In rat and human platelets, agonist-induced platelet aggregation was significantly increased by salsolinol in a concentration-dependent manner. Agonist-induced granular secretions of serotonin and concomitant P-selectin expression were also augmented by salsolinol. α2-adrenergic blockers attenuated the salsolinol-enhanced aggregation and the inhibition of cyclic AMP generation was found, suggesting the involvement of α2-adrenergic receptor-mediated pathways in these events. In accord with the in-vitro results, in an arterial and venous thrombosis model in vivo in the rat, salsolinol shortened vessel occlusion time and increased thrombus formation, respectively. In conclusion, we demonstrated that sal-solinol can enhance agonist-induced aggregation and granular secretion in platelets through α2-adrenergic receptor activation, which resulted in the increased thrombus formation in vivo.These results suggest that salsolinol-enhanced platelet aggregation could be a possible contributing factor to the thrombotic events observed in Parkinson’s disease and alcoholism.

scholarly journals New Insights into Immune-Mediated Mechanisms in Parkinson’s Disease

2020 ◽  
Vol 21 (23) ◽  
pp. 9302
Author(s):  
Jolene Su Yi Tan ◽  
Yin Xia Chao ◽  
Olaf Rötzschke ◽  
Eng-King Tan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Immune System ◽  
Neuronal Death ◽  
Dopaminergic Neurons ◽  
Adaptive Immune ◽  
Immune Mediators ◽  
Immune Mediated ◽  
Neuroprotective Strategies ◽  
Immunomodulatory Therapies

The immune system has been increasingly recognized as a major contributor in the pathogenesis of Parkinson’s disease (PD). The double-edged nature of the immune system poses a problem in harnessing immunomodulatory therapies to prevent and slow the progression of this debilitating disease. To tackle this conundrum, understanding the mechanisms underlying immune-mediated neuronal death will aid in the identification of neuroprotective strategies to preserve dopaminergic neurons. Specific innate and adaptive immune mediators may directly or indirectly induce dopaminergic neuronal death. Genetic factors, the gut-brain axis and the recent identification of PD-specific T cells may provide novel mechanistic insights on PD pathogenesis. Future studies to address the gaps in the identification of autoantibodies, variability in immunophenotyping studies and the contribution of gut dysbiosis to PD may eventually provide new therapeutic targets for PD.

scholarly journals Mulberry fruit protects dopaminergic neurons in toxin-induced Parkinson's disease models

2010 ◽  
Vol 104 (1) ◽  
pp. 8-16 ◽  
Author(s):  
Hyo Geun Kim ◽  
Mi Sun Ju ◽  
Jin Sup Shim ◽  
Min Cheol Kim ◽  
Sang-Hun Lee ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Dependent Manner ◽  
Mulberry Fruit ◽  
Wide Range

Parkinson's disease (PD), one of the most common neurodegenerative disorders, is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) to the striatum (ST), and involves oxidative stress. Mulberry fruit fromMorus albaL. (Moraceae) is commonly eaten, and has long been used in traditional oriental medicine. It contains well-known antioxidant agents such as anthocyanins. The present study examined the protective effects of 70 % ethanol extract of mulberry fruit (ME) against neurotoxicity inin vitroandin vivoPD models. In SH-SY5Y cells stressed with 6-hydroxydopamine (6-OHDA), ME significantly protected the cells from neurotoxicity in a dose-dependent manner. Other assays demonstrated that the protective effect of ME was mediated by its antioxidant and anti-apoptotic effects, regulating reactive oxygen species and NO generation, Bcl-2 and Bax proteins, mitochondrial membrane depolarisation and caspase-3 activation. In mesencephalic primary cells stressed with 6-OHDA or 1-methyl-4-phenylpyridinium (MPP+), pre-treatment with ME also protected dopamine neurons, showing a wide range of effective concentrations in MPP+-induced toxicity. In the sub-acute mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), ME showed a preventative effect against PD-like symptoms (bradykinesia) in the behavioural test and prevented MPTP-induced dopaminergic neuronal damage in an immunocytochemical analysis of the SNpc and ST. These results indicate that ME has neuroprotective effects inin vitroandin vivoPD models, and that it may be useful in preventing or treating PD.

scholarly journals Alpha-synuclein enhances lipid droplet accumulation in neurons in a Drosophila model of Parkinson’s disease

2020 ◽  
Author(s):  
Victor Girard ◽  
Florence Jollivet ◽  
Oskar Knittelfelder ◽  
Jean-Noel Arsac ◽  
Gilles Chatelain ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
De Novo ◽  
Neurodegenerative Disorder ◽  
Neuroblastoma Cells ◽  
Alpha Synuclein ◽  
Human Neuroblastoma ◽  
Drosophila Model ◽  
Human Neurons ◽  
Photoreceptor Neurons

AbstractParkinson’s disease is a neurodegenerative disorder characterized by accumulation of alpha-synuclein (αSyn) aggregates and by abnormalities in lipid storage. To investigate the potential pathophysiological consequences of interactions between αSyn and proteins that regulate the homeostasis of intracellular lipid droplets (LDs), we employed a transgenic Drosophila model of PD in which human αSyn is specifically expressed in photoreceptor neurons. We found that overexpression of the LD-coating proteins perilipin 1 and 2 (dPlin1/2) markedly increased LD accumulation in the neurons. Perilipins also co-localized with αSyn at the LD surface in both Drosophila photoreceptor neurons (dPlin2) and human neuroblastoma cells (PLIN3). Co-expression of αSyn and dPlin2 in photoreceptor neurons synergistically amplified LD content through a mechanism involving LD stabilization, independently of Brummer-mediated lipolysis or de novo synthesis of triacylglycerols. Accumulation of LDs also increased the resistance of αSyn to proteolytic digestion, a phenomenon associated with αSyn aggregation in human neurons. Our results suggest that binding of αSyn to PLIN-coated LDs stabilizes the LD structure and may contribute to the pathogenic misfolding and aggregation of αSyn in neurons.

Cutaneous Sympathetic Vasoconstrictor Function in Multiple System Atrophy and Parkinson's Disease

2004 ◽  
Vol 35 (03) ◽  
Author(s):  
G Wasner ◽  
P Remien ◽  
C Guballa ◽  
M Hirschner ◽  
A Binder ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Multiple System Atrophy

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.

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