scholarly journals The selective degradation of sirtuins via macroautophagy in the MPP+ model of Parkinson’s disease is promoted by conserved oxidation sites

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Marius W. Baeken ◽  
Mario Schwarz ◽  
Andreas Kern ◽  
Bernd Moosmann ◽  
Parvana Hajieva ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Metabolic Regulation ◽  
Dna Interaction ◽  
Radical Scavenger ◽  
Dependent Manner ◽  
Cysteine Oxidation ◽  
Wide Range ◽  
Protein Properties

AbstractThe sirtuin (SIRT) protein family has been of major research interest over the last decades because of their involvement in aging, cancer, and cell death. SIRTs have been implicated in gene and metabolic regulation through their capacity to remove acyl groups from lysine residues in proteins in an NAD+-dependent manner, which may alter individual protein properties as well as the histone–DNA interaction. Since SIRTs regulate a wide range of different signaling cascades, a fine-tuned homeostasis of these proteins is imperative to guarantee the function and survival of the cell. So far, however, how exactly this homeostasis is established has remained unknown. Here, we provide evidence that neuronal SIRT degradation in Parkinson’s disease (PD) models is executed by autophagy rather than the proteasome. In neuronal Lund human mesencephalic (LUHMES) cells, all seven SIRTs were substrates for autophagy and showed an accelerated autophagy-dependent degradation upon 1-methyl-4-phenylpyridinium (MPP+) mediated oxidative insults in vitro, whereas the proteasome did not contribute to the removal of oxidized SIRTs. Through blockade of endogenous H2O2 generation and supplementation with the selective radical scavenger phenothiazine (PHT), we could identify H2O2-derived species as the responsible SIRT-oxidizing agents. Analysis of all human SIRTs suggested a conserved regulatory motif based on cysteine oxidation, which may have triggered their degradation via autophagy. High amounts of H2O2, however, rapidly carbonylated selectively SIRT2, SIRT6, and SIRT7, which were found to accumulate carbonylation-prone amino acids. Our data may help in finding new strategies to maintain and modify SIRT bioavailability in neurodegenerative disorders.

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 Crocetin Alleviates Inflammation in MPTP-Induced Parkinson’s Disease Models through Improving Mitochondrial Functions

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Na Dong ◽  
Zhong Dong ◽  
Ying Chen ◽  
Xiaosu Gu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Permeability Transition ◽  
Therapeutic Potential ◽  
Adenine Nucleotide ◽  
Motor Deficits ◽  
Dependent Manner ◽  
Cyclophilin D ◽  
Mitochondrial Functions

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Crocetin, derived from saffron, exerts multiple pharmacological properties, such as anti-inflammatory, antioxidant, antifatigue, and anticancer effects. However, the effect of crocetin on PD remains unclear. In this study, we designed experiments to investigate the effect of crocetin against MPTP-induced PD models and the underlying mechanisms. Our results showed that crocetin treatment attenuates MPTP-induced motor deficits and protects dopaminergic neurons. Both in vivo and in vitro experiments demonstrated that crocetin treatment decreased the expression of inflammatory associated genes and inflammatory cytokines. Furthermore, crocetin treatment protected mitochondrial functions against MPP+ induced damage by regulating the mPTP (mitochondrial permeability transition pore) viability in the interaction of ANT (adenine nucleotide translocase) and Cyp D (Cyclophilin D) dependent manner. Therefore, our results demonstrate that crocetin has therapeutic potential in Parkinson’s disease.

Arylsulfatase A, a genetic modifier of Parkinson’s disease, is an α-synuclein chaperone

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2845-2859 ◽  
Author(s):  
Jun Sung Lee ◽  
Kazuaki Kanai ◽  
Mari Suzuki ◽  
Woojin S Kim ◽  
Han Soo Yoo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Modifier ◽  
Ectopic Expression ◽  
Physical Interaction ◽  
Dependent Manner ◽  
Arylsulfatase A ◽  
Lysosomal Storage ◽  
Protein Levels

AbstractMutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson’s disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson’s disease. Plasma ARSA protein levels were changed in Parkinson’s disease patients. ARSA deficiency caused increases in α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson’s disease pathogenesis, acting as a molecular chaperone for α-synuclein.

scholarly journals Cerium Oxide Nanoparticles Rescue α-Synuclein-Induced Toxicity in a Yeast Model of Parkinson’s Disease

Nanomaterials ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 235 ◽  
Author(s):  
Roberta Ruotolo ◽  
Giuseppe De Giorgio ◽  
Ilaria Minato ◽  
Massimiliano Bianchi ◽  
Ovidio Bussolati ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cerium Oxide ◽  
Yeast Cells ◽  
Cerium Oxide Nanoparticles ◽  
Radical Scavenger ◽  
Oxide Nanoparticles ◽  
Dependent Manner ◽  
Strong Inhibitor ◽  
Yeast Model

Over the last decades, cerium oxide nanoparticles (CeO2 NPs) have gained great interest due to their potential applications, mainly in the fields of agriculture and biomedicine. Promising effects of CeO2 NPs are recently shown in some neurodegenerative diseases, but the mechanism of action of these NPs in Parkinson’s disease (PD) remains to be investigated. This issue is addressed in the present study by using a yeast model based on the heterologous expression of the human α-synuclein (α-syn), the major component of Lewy bodies, which represent a neuropathological hallmark of PD. We observed that CeO2 NPs strongly reduce α-syn-induced toxicity in a dose-dependent manner. This effect is associated with the inhibition of cytoplasmic α-syn foci accumulation, resulting in plasma membrane localization of α-syn after NP treatment. Moreover, CeO2 NPs counteract the α-syn-induced mitochondrial dysfunction and decrease reactive oxygen species (ROS) production in yeast cells. In vitro binding assay using cell lysates showed that α-syn is adsorbed on the surface of CeO2 NPs, suggesting that these NPs may act as a strong inhibitor of α-syn toxicity not only acting as a radical scavenger, but through a direct interaction with α-syn in vivo.

scholarly journals Biodegradable nanoparticles loaded with levodopa and/or curcumin for treatment of Parkinson’s disease

2021 ◽  
Vol 31 (Supplement_2) ◽  
Author(s):  
Marco André Cardoso ◽  
Bassam Felipe Mogharbel ◽  
Ana Carolina Irioda ◽  
Priscila Elias Ferreira Stricker ◽  
Robson Camilotti Slompo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Pc12 Cells ◽  
Neurodegenerative Disorder ◽  
Toxicity Testing ◽  
In Vitro Toxicity ◽  
Age Related ◽  
Wide Range ◽  
Low Cytotoxicity

Abstract Background Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder. Levodopa (L-DOPA) remains the standard gold drug available for the treatment of PD. Curcumin has a wide range of pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, anti-amyloid, antitumor properties. Copolymers composed of poly(ethylene oxide) (PEO) and biodegradable polyesters like poly(ε-caprolactone) (PCL) that can self-assemble into nanoparticles (NP). This study describes the development of NH2-PEO-PCL diblock copolymer positively charged and modified by the addition of glutathione (GSH) on the outer surface, resulting in a synergistic delivery of L-DOPA and curcumin that would be able to pass the blood-brain barrier. Methods The NH2-PEO-PCL nanoparticles suspensions were prepared using a nanoprecipitation and solvent displacement method and were coated with GSH. NP was submitted to various characterizations assays, and to ensure the bioavailability, Vero and PC12 cells were treated with various concentrations of the loaded and unloaded NP to observe cytotoxicity. Results NP has successfully loaded L-DOPA and curcumin was stable after freeze-drying, capable of advancing into in vitro toxicity testing. After being treated up to 72 hours of various concentrations of L-DOPA and curcumin loaded NP Vero and PC12 cells, the viability of the treated cells maintained a high percentage indicating that the NPs are biocompatible. Conclusions NP consisting of NH2-PEO-PCL have been characterized as potential formulations for brain delivery of L-DOPA and curcumin, and obtained results also indicate that the developed biodegradable nanomicelles were blood compatible, presented low cytotoxicity even in longer exposure times.

scholarly journals MiR-30a-5p regulates GLT-1 function via a PKCα-mediated ubiquitin degradation pathway in a mouse model of Parkinson’s disease

2020 ◽  
Author(s):  
Xingjun Meng ◽  
Jianping Zhong ◽  
Chong Zeng ◽  
Ken Kin Lam Yung ◽  
Xiuping Zhang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Cell Model ◽  
Glutamate Transporters ◽  
Acid Uptake ◽  
Dependent Manner ◽  
The Impact

Abstract Background:Glutamate excitotoxicity caused by dysfunctional glutamate transporters plays an important role in the pathogenesis of Parkinson’s disease (PD); however, the mechanisms that underlie the regulation of glutamate transporters in PD are still not fully elucidated. MicroRNAs have been reported to play key roles in regulating the translation of glutamate-transporter mRNA. Methods: We established model of PD 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice in vivo and 1-methyl-4-phenylpyridinium (MPP+) treated astrocyte in vitro. Stereotaxic injection of shRNA in mouse, and miRNA inhibitor/mimic, or antagonist/agonist treated the cell model, Behavioral experiments, glutamic acid uptake, transport activity of synaptosomes, underlying mechanisms and the impact on neuronal survival were assessed.Results We demonstrated that short-hairpin RNA-mediated knockdown of miR-30a-5p ameliorated motor deficits and pathological changes like astrogliosis and reactive microgliosis in a mouse model of PD. Western blotting and immunofluorescent labeling revealed that miR-30a-5p suppressed the expression and function of GLT-1 in MPTP-treated mice and specifically in astrocytes treated with (cell model of PD). Conclusion Both in vitro and in vivo, we found that miR-30a-5p knockdown promoted glutamate uptake and increased GLT-1 expression by hindering GLT-1 ubiquitination and subsequent degradation in a PKCα-dependent manner. Therefore, miR-30a-5p represents a potential therapeutic target for the treatment of PD.

scholarly journals Tetramethylpyrazine nitrone exerts neuroprotection via PGC-1α/Nrf2 activation and α-synuclein clearance in Parkinson’s disease models

2020 ◽  
Author(s):  
Baojian Guo ◽  
Chengyou Zheng ◽  
Jie Cao ◽  
Shangming Li ◽  
Fangcheng Luo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mice ◽  
Dopaminergic Neurons ◽  
Radical Scavenger ◽  
Related Factor ◽  
Mice Model ◽  
Mitochondrial Functions ◽  
Nrf2 Signaling Pathway

Abstract Background: The peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and Nuclear factor erythroid 2-related factor 2 (Nrf2) are key regulators controlling antioxidant defense, mitochondrial biogenesis and cellular proteostasis. Dysfunction of these processes has been implicated in the pathogenesis of Parkinson’s disease (PD). Activation of PGC-1α/Nrf2 might improve mitochondrial dysfunction, promote α-synuclein (α-syn) clearance and attenuate degeneration of nigral dopaminergic neurons in PD. Methods: Neurotoxin-induced in vitro PD model, 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated mice model, unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA)-lesioned rat model, and transgenic mice overexpression of human A53T mutant α-synuclein were used to evaluate the neuroprotective and neurorescue effect of tetramethylpyrazine nitrone (TBN), a free radical scavenger, and its regulation on PGC-1α/Nrf2 pathway. Results: TBN protected against 1-methyl-4-phenylpyridinium (MPP + ) and 6-OHDA insult in cultured primary midbrain neurons. TBN promoted α-syn clearance by autophagy and proteasomal pathways in cell models overexpressing the human A53T mutant α-syn. In MPTP-treated mice, unilateral 6-OHDA-lesioned rats, and the α-syn transgenic mice model, TBN improved motor impairment, increased survival of nigral dopaminergic neurons, and elevated striatal dopamine levels while decreasing the products of oxidative damage. Importantly, TBN down-regulated the α-syn level in the brain and serum of α-syn-transgenic mice. These in vitro and in vivo improvements were associated with activation of the PGC-1α/Nrf2 signaling pathway, resulting in reduced oxidative stress, and enhanced mitochondrial functions. Conclusions: Our work demonstrates that TBN activates PGC-1α/Nrf2 and increases the survival of nigral dopaminergic neurons. These results suggest that TBN warrants further development as a potential new PD treatment.

scholarly journals 2-Hydroxy-4-Methylbenzoic Anhydride Inhibits Neuroinflammation in Cellular and Experimental Animal Models of Parkinson’s Disease

2020 ◽  
Vol 21 (21) ◽  
pp. 8195
Author(s):  
Soo-Yeol Song ◽  
In-Su Kim ◽  
Sushruta Koppula ◽  
Ju-Young Park ◽  
Byung-Wook Kim ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Parent Compound ◽  
Intraperitoneal Administration ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Protein Levels

Microglia-mediated neuroinflammation is one of the key mechanisms involved in acute brain injury and chronic neurodegeneration. This study investigated the inhibitory effects of 2-hydroxy-4-methylbenzoic anhydride (HMA), a novel synthetic derivative of HTB (3-hydroxy-4-trifluoromethylbenzoic acid) on neuroinflammation and underlying mechanisms in activated microglia in vitro and an in vivo mouse model of Parkinson’s disease (PD). In vitro studies revealed that HMA significantly inhibited lipopolysaccharide (LPS)-stimulated excessive release of nitric oxide (NO) in a concentration dependent manner. In addition, HMA significantly suppressed both inducible NO synthase and cyclooxygenase-2 (COX-2) at the mRNA and protein levels in LPS-stimulated BV-2 microglia cells. Moreover, HMA significantly inhibited the proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in LPS-stimulated BV-2 microglial cells. Furthermore, mechanistic studies ensured that the potent anti-neuroinflammatory effects of HMA (0.1, 1.0, and 10 μM) were mediated by phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) in LPS-stimulated BV-2 cells. In vivo evaluations revealed that intraperitoneal administration of potent neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg, four times a 1 day) in mice resulted in activation of microglia in the brain in association with severe behavioral deficits as assessed using a pole test. However, prevention of microglial activation and attenuation of Parkinson’s disease (PD)-like behavioral changes was obtained by oral administration of HMA (30 mg/kg) for 14 days. Considering the overall results, our study showed that HMA exhibited strong anti-neuroinflammatory effects at lower concentrations than its parent compound. Further work is warranted in other animal and genetic models of PD for evaluating the efficacy of HMA to develop a potential therapeutic agent in the treatment of microglia-mediated neuroinflammatory disorders, including PD.

Design, Optimization and Evaluation of Fast-Dissolving Oral Films of Ropinirole

2018 ◽  
Vol 11 (1) ◽  
pp. 3958-3967
Author(s):  
Bhikshapathi D. V. R. N. ◽  
Srinivas A
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Good Alternative ◽  
In Vitro Dissolution ◽  
Content Uniformity ◽  
Onset Of Action ◽  
Disintegration Time ◽  
Peg 4000 ◽  
Oral Films

The main objective of this study was to develop fast dissolving oral films of ropinirole HCl to attain quick onset of action for the better management of Parkinson’s disease. Twenty-seven formulations (F1-F27) of ropinirole oral dissolving films by solvent-casting method using 33 response surface method by using HPMC E15, Maltodextrin PEG 4000 by using Design of experiment software. Formulations were evaluated for their physical characteristics, thickness, folding endurance, tensile strength, disintegration time, drug content uniformity and drug release characteristics and found to be within the limits. Among the prepared formulations F4 showed minimum disintegration time 11 sec, maximum drug was released i.e. 99.68 ± 1.52% of drug within 10 min when compared to the other formulations and finalized as optimized formulation. FTIR data revealed that no interactions takes place between the drug and polymers used in the optimized formulation. The in vitro dissolution profiles of marketed product and optimized formulation was compared and found to be the drug released was 92.77 ± 1.52 after 50 min. Therefore, it can be a good alternative to conventional ropinirole for immediate action. In vitro evaluation of the ropinirole fast dissolving films confirmed their potential as an innovative dosage form to improve delivery and quick onset of action of ropinirole. The oral dissolving film is considered to be potentially useful for the treatment of Parkinson’s disease where quick onset of action is desired

Sign in / Sign up

Export Citation Format

Share Document