scholarly journals Targeting Histone Deacetylases: A Novel Approach in Parkinson’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Sorabh Sharma ◽  
Rajeev Taliyan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
Hdac Inhibitors ◽  
Clinical Manifestations ◽  
Future Research

The worldwide prevalence of movement disorders is increasing day by day. Parkinson’s disease (PD) is the most common movement disorder. In general, the clinical manifestations of PD result from dysfunction of the basal ganglia. Although the exact underlying mechanisms leading to neural cell death in this disease remains unknown, the genetic causes are often established. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the neurological disease conditions. The acetylation and deacetylation of histone proteins are carried out by opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the recent past, studies with HDAC inhibitors result in beneficial effects in bothin vivoandin vitromodels of PD. Various clinical trials have also been initiated to investigate the possible therapeutic potential of HDAC inhibitors in patients suffering from PD. The possible mechanisms assigned for these neuroprotective actions of HDAC inhibitors involve transcriptional activation of neuronal survival genes and maintenance of histone acetylation homeostasis, both of which have been shown to be dysregulated in PD. In this review, the authors have discussed the putative role of HDAC inhibitors in PD and associated abnormalities and suggest new directions for future research in PD.

scholarly journals CRISPR/Cas9-mediated gene editing induces neurological recovery in an A53T-SNCA overexpression rat model of Parkinson’s disease

2020 ◽  
Author(s):  
Hyung Ho Yoon ◽  
Sunghyeok Ye ◽  
Sunhwa Lim ◽  
Seung Eun Lee ◽  
Soo-Jin Oh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Therapeutic Potential ◽  
Negative Control ◽  
Adeno Associated Virus ◽  
Guide Rna ◽  
Dopaminergic Neurodegeneration

AbstractTo date, no publicly available disease-modifying therapy for Parkinson’s disease has been developed. This can be partly attributed to the absence of techniques for in vivo deletion of the SNCA gene (encoding α-synuclein), which is one of the key players in Parkinson’s disease pathology. In particular, A53T-mutated SNCA (A53T-SNCA) is one of the most studied familial pathologic mutations in Parkinson’s disease. Here we utilized a recently discovered genome editing technique, CRISPR/Cas9, to delete A53T-SNCA in vitro and in vivo. Among various CRISPR/Cas9 systems, SaCas9-KKH with a single guide RNA (sgRNA) targeting A53T-SNCA was packaged into adeno-associated virus. Adeno-associated virus carrying SaCas9-KKH significantly reduced A53T-SNCA levels in A53T-SNCA-overexpressed HEK293T cells, without off-target effects on wild-type SNCA. Furthermore, we tested the technique’s in vivo therapeutic potential in a viral A53T-SNCA overexpression rat model of Parkinson’s disease. Gene deletion of A53T-SNCA significantly prevented the overexpression of α-synuclein, dopaminergic neurodegeneration, and parkinsonian motor symptoms, whereas a negative control without sgRNA did not. Our findings propose CRISPR/Cas9 system as a potential therapeutic tool for A53T-SNCA familial Parkinson’s disease.

The Critical Role of Glutamine Transporter ASCT2 in Parkinson’s Disease Progression

2021 ◽  
Author(s):  
Rohit Mantena ◽  
Donna Leonardi
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Regression Model ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Competitive Inhibitor ◽  
Future Research ◽  
Glutamine Uptake

Abstract Parkinson’s Disease (PD) is the second most common neurodegenerative disease, and it plagues millions of people worldwide. PD presents with the loss of dopaminergic neurons, associated with increased oxidative stress. Glutathione (GSH) is a prominent antioxidant; in PD, however, GSH levels are significantly diminished. A precursor for GSH is the amino acid glutamine, which is converted to glutamate and then to GSH. The carrier for glutamine is a transport membrane protein, named ASCT2, and this protein regulates glutamine uptake. In various forms of cancer, inhibition of ASCT2 has led to oxidative stress-mediated apoptosis.This research looked to elucidate the role ASCT2 can play in PD progression by using α-synuclein transfected SH-SY5Y neurons as an in vitro model of PD. V-9302 is a competitive inhibitor of ASCT2 and was used to diminish ASCT2 transport and glutamine uptake to examine the in vitro hallmarks of PD progression. Increasing V-9302 concentrations (decreased ASCT2 activity) led to lower cell viability, higher ROS levels, and higher α-synuclein levels. Also, increasing V-9302 concentrations led to a decrease in intracellular glutamine, glutamate, and GSH levels. In addition, a power regression model was generated for each of glutamine, glutamate, and GSH vs α-synuclein to test the biomarker potential of each of these molecules for PD progression. Each of these molecules fit the regression model extraordinarily. The findings suggest that inhibition of ASCT2 lead to the heightened hallmarks of PD progression. Future research could examine the exciting therapeutic potential of upregulating ASCT2 on PD progression.

scholarly journals Grafts Derived from an α-Synuclein Triplication Patient Mediate Functional Recovery but Develop Disease-Associated Pathology in the 6-OHDA Model of Parkinson’s Disease

2020 ◽  
pp. 1-14
Author(s):  
Shelby Shrigley ◽  
Fredrik Nilsson ◽  
Bengt Mattsson ◽  
Alessandro Fiorenzano ◽  
Janitha Mudannayake ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Lines ◽  
Functional Recovery ◽  
Embryonic Stem ◽  
Hesc Line ◽  
Alternative Source ◽  
And Function

Background: Human induced pluripotent stem cells (hiPSCs) have been proposed as an alternative source for cell replacement therapy for Parkinson’s disease (PD) and they provide the option of using the patient’s own cells. A few studies have investigated transplantation of patient-derived dopaminergic (DA) neurons in preclinical models; however, little is known about the long-term integrity and function of grafts derived from patients with PD. Objective: To assess the viability and function of DA neuron grafts derived from a patient hiPSC line with an α-synuclein gene triplication (AST18), using a clinical grade human embryonic stem cell (hESC) line (RC17) as a reference control. Methods: Cells were differentiated into ventral mesencephalic (VM)-patterned DA progenitors using an established GMP protocol. The progenitors were then either terminally differentiated to mature DA neurons in vitro or transplanted into 6-hydroxydopamine (6-OHDA) lesioned rats and their survival, maturation, function, and propensity to develop α-synuclein related pathology, were assessed in vivo. Results: Both cell lines generated functional neurons with DA properties in vitro. AST18-derived VM progenitor cells survived transplantation and matured into neuron-rich grafts similar to the RC17 cells. After 24 weeks, both cell lines produced DA-rich grafts that mediated full functional recovery; however, pathological changes were only observed in grafts derived from the α-synuclein triplication patient line. Conclusion: This data shows proof-of-principle for survival and functional recovery with familial PD patient-derived cells in the 6-OHDA model of PD. However, signs of slowly developing pathology warrants further investigation before use of autologous grafts in patients.

scholarly journals Neuroprotective Effect of Optimized Yinxieling Formula in 6-OHDA-Induced Chronic Model of Parkinson’s Disease through the Inflammation Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Renrong Wei ◽  
Cuiping Rong ◽  
Qingfeng Xie ◽  
Shouhai Wu ◽  
Yuchao Feng ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Calcium Binding ◽  
Dopaminergic Neurons ◽  
Neuroprotective Effect ◽  
Interleukin 1 ◽  
Mrna Levels ◽  
Cox 2

Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN)-striatum circuit, which is associated with glial activation and consequent chronic neuroinflammation. Optimized Yinxieling Formula (OYF) is a Chinese medicine that exerts therapeutical effect and antiinflammation property on psoriasis. Our previous study has proven that pretreatment with OYF could regulate glia-mediated inflammation in an acute mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Given that PD is a chronic degeneration disorder, this study applied another PD animal model induced by striatal injection of 6-hydroxydopamine (6-OHDA) to mimic the progressive damage of the SN-striatum dopamine system in rats. The OYF was administrated in the manner of pretreatment plus treatment. The effects of the OYF on motor behaviors were assessed with the apomorphine-induced rotation test and adjusting steps test. To confirm the effect of OYF on dopaminergic neurons and glia activation in this model, we analyzed the expression of tyrosine hydroxylase (TH) and glia markers, ionized calcium-binding adapter molecule 1 (Iba-1), and glial fibrillary acidic protein (GFAP) in the SN region of the rat PD model. Inflammation-associated factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), were further evaluated in this model and in interferon-γ- (INF-γ-) induced murine macrophages RAW264.7 cells. The results from the in vivo study showed that OYF reversed the motor behavioral dysfunction in 6-OHDA-induced PD rats, upregulated the TH expression, decreased the immunoreactivity of Iba-1 and GFAP, and downregulated the mRNA levels of TNF-α and COX-2. The OYF also trended to decrease the mRNA levels of IL-1β and iNOS in vivo. The results from the in vitro study showed that OYF significantly decreased the mRNA levels of TNF-α, IL-1β, IL-6, iNOS, and COX-2. Therefore, this study suggests that OYF exerts antiinflammatory effects, which might be related to the protection of dopaminergic neurons in 6-OHDA-induced chronic neurotoxicity.

Simvastatin Prevents Neurodegeneration in the MPTP Mouse Model of Parkinson’s Disease via Inhibition of A1 Reactive Astrocytes

2021 ◽  
pp. 1-8
Author(s):  
Ren-Wei Du ◽  
Wen-Guang Bu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Underlying Mechanism ◽  
Reactive Astrocytes ◽  
Dopamine Neurons ◽  
Neuron Death ◽  
Neurologic Disorders

Emerging evidence indicates that A1 reactive astrocytes play crucial roles in the pathogenesis of Parkinson’s disease (PD). Thus, development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat PD. Simvastatin has been touted as a potential neuroprotective agent for neurologic disorders such as PD, but the specific underlying mechanism remains unclear. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and primary astrocytes/neurons were prepared to investigate the effects of simvastatin on PD and its underlying mechanisms in vitro and in vivo. We show that simvastatin protects against the loss of dopamine neurons and behavioral deficits in the MPTP mouse model of PD. We also found that simvastatin suppressed the expression of A1 astrocytic specific markers in vivo and in vitro. In addition, simvastatin alleviated neuron death induced by A1 astrocytes. Our findings reveal that simvastatin is neuroprotective via the prevention of conversion of astrocytes to an A1 neurotoxic phenotype. In light of simvastatin favorable properties, it should be evaluated in the treatment of PD and related neurologic disorders characterized by A1 reactive astrocytes.

Pharmacological Blocker of NF-κb and Mitochondrial Ros Restrict NLRP3 Inflammasome Activation and Rescue Dopaminergic Neurons in Vitro and in Vivo Parkinson’s Disease

2021 ◽  
Author(s):  
Sahabuddin Ahmed ◽  
Samir Ranjan Panda ◽  
Mohit Kwatra ◽  
Bidya Dhar Sahu ◽  
VGM Naidu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Free Radicals ◽  
Nlrp3 Inflammasome ◽  
Nuclear Translocation ◽  
Inflammasome Activation ◽  
Mitochondrial Ros ◽  
Nlrp3 Inflammasome Activation

Abstract Several activators of NLRP3 inflammasome have been described; however, the central mechanisms of NLRP3 inflammasome activation in brain microglia, especially at the activating step through free radical generation, still require further clarification. Hence the present study aimed to investigate the role of free radicals in activating NLRP3 inflammasome driven neurodegeneration and elucidated the neuroprotective role of perillyl alcohol (PA) in vitro and in vivo models of Parkinson’s disease. Initial priming of microglial cells with lipopolysaccharide (LPS) following treatment with hydrogen peroxide (H2O2) induces NF-κB translocation to nucleus with robust generation of free radicals that act as Signal 2 in augmenting NLRP3 inflammasome assembly and its downstream targets. PA treatment suppresses nuclear translocation of NF-κB and maintains cellular redox homeostasis in microglia that limits NLRP3 inflammasome activation along with processing active caspase-1, IL-1β and IL-18. To further correlates the in vitro study with in vivo MPTP model, treatment with PA also inhibits the nuclear translocation of NF-κB and downregulates the NLRP3 inflammasome activation. PA administration upregulates various antioxidant enzymes levels and restored the level of dopamine and other neurotransmitters in the striatum of the mice brain with improved behavioural activities. Additionally, treatment with Mito-TEMPO (a mitochondrial ROS inhibitor) was also seen to inhibit NLRP3 inflammasome and rescue dopaminergic neuron loss in the mice brain. Therefore, we conclude that NLRP3 inflammasome activation requires a signal from damaged mitochondria for its activation. Further pharmacological scavenging of free radicals restricts microglia activation and simultaneously supports neuronal survival via targeting NLRP3 inflammasome pathway in Parkinson’s disease.

BAG1 is Neuroprotective in In Vivo and In Vitro Models of Parkinson’s Disease

2014 ◽  
Vol 55 (3) ◽  
pp. 587-595 ◽  
Author(s):  
Pawel Kermer ◽  
Anja Köhn ◽  
Marlena Schnieder ◽  
Paul Lingor ◽  
Mathias Bähr ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
In Vitro Models

scholarly journals Protective effects of saffron and its constituent crocetin to motor symptoms, short life span and rough-eyed phenotypes in the fly models of Parkinson’s disease in vivo

2020 ◽  
Author(s):  
Eiji Inoue ◽  
Takahiro Suzuki ◽  
Yasuharu Shimizu ◽  
Keiichi Sudo ◽  
Haruhisa Kawasaki ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Life Span ◽  
Neurodegenerative Disorder ◽  
Neuronal Cell ◽  
Crocus Sativus ◽  
Motor Symptoms ◽  
Protective Effects

AbstractParkinson’s disease (PD) is a common neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the brain. α-Synuclein is an aggregation-prone neural protein that plays a role in the pathogenesis of PD. In our previous paper, we found that saffron; the stigma of Crocus sativus Linné (Iridaceae), and its constituents (crocin and crocetin) suppressed aggregation of α-synuclein and promoted the dissociation of α-synuclein fibrils in vitro. In this study, we investigated the effect of dietary saffron and its constituent, crocetin, in vivo on a fly PD model overexpressing several mutant α-synuclein in a tissue-specific manner. Saffron and crocetin significantly suppressed the decrease of climbing ability in the Drosophila overexpressing A30P (A30P fly PD model) or G51D (G51D fly PD model) mutated α-synuclein in neurons. Saffron and crocetin extended the life span in the G51D fly PD model. Saffron suppressed the rough-eyed phenotype and the dispersion of the size histogram of the ocular long axis in A30P fly PD model in eye. Saffron had a cytoprotective effect on a human neuronal cell line with α-synuclein fibrils. These data showed that saffron and its constituent crocetin have protective effects on the progression of PD disease in animals in vivo and suggest that saffron and crocetin can be used to treat PD.

scholarly journals Inhibition of EZH2 by chidamide exerts antileukemia activity and increases chemosensitivity through Smo/Gli-1 pathway in acute myeloid leukemia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xuejie Jiang ◽  
Ling Jiang ◽  
Jiaying Cheng ◽  
Fang Chen ◽  
Jinle Ni ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Histone Deacetylases ◽  
Myeloid Leukemia ◽  
Hdac Inhibitors ◽  
Annexin V ◽  
Fluorescein Isothiocyanate ◽  
Gli 1 ◽  
Acute Myeloid

Abstract Background Epigenetic dysregulation plays important roles in leukemogenesis and the progression of acute myeloid leukemia (AML). Histone acetyltransferases (HATs) and histone deacetylases (HDACs) reciprocally regulate the acetylation and deacetylation of nuclear histones. Aberrant activation of HDACs results in uncontrolled proliferation and blockade of differentiation, and HDAC inhibition has been investigated as epigenetic therapeutic strategy against AML. Methods Cell growth was assessed with CCK-8 assay, and apoptosis was evaluated by flow cytometry in AML cell lines and CD45 + and CD34 + CD38- cells from patient samples after staining with Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI). EZH2 was silenced with short hairpin RNA (shRNA) or overexpressed by lentiviral transfection. Changes in signaling pathways were detected by western blotting. The effect of chidamide or EZH2-specific shRNA (shEZH2) in combination with adriamycin was studied in vivo in leukemia-bearing nude mouse models. Results In this study, we investigated the antileukemia effects of HDAC inhibitor chidamide and its combinatorial activity with cytotoxic agent adriamycin in AML cells. We demonstrated that chidamide suppressed the levels of EZH2, H3K27me3 and DNMT3A, exerted potential antileukemia activity and increased the sensitivity to adriamycin through disruption of Smo/Gli-1 pathway and downstream signaling target p-AKT in AML cells and stem/progenitor cells. In addition to decreasing the levels of H3K27me3 and DNMT3A, inhibition of EZH2 either pharmacologically by chidamide or genetically by shEZH2 suppressed the activity of Smo/Gli-1 pathway and increased the antileukemia activity of adriamycin against AML in vitro and in vivo. Conclusions Inhibition of EZH2 by chidamide has antileukemia activity and increases the chemosensitivity to adriamycin through Smo/Gli-1 pathway in AML cells (Fig. 5). These findings support the rational combination of HDAC inhibitors and chemotherapy for the treatment of AML.

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