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.

scholarly journals Norfluoxetine Prevents Degeneration of Dopamine Neurons by Inhibiting Microglia-Derived Oxidative Stress in an MPTP Mouse Model of Parkinson’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-8
Author(s):  
Kyung In Kim ◽  
Young Cheul Chung ◽  
Byung Kwan Jin
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Microglial Activation ◽  
Dopamine Neurons ◽  
Activated Microglia ◽  
Nigrostriatal Dopamine Neurons

Neuroinflammation is the neuropathological feature of Parkinson’s disease (PD) and causes microglial activation and activated microglia-derived oxidative stress in the PD patients and PD animal models, resulting in neurodegeneration. The present study examined whether norfluoxetine (a metabolite of fluoxetine) could regulate neuroinflammation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD and rescue dopamine neurons. Analysis by tyrosine hydroxylase (TH) immunohistochemistry demonstrated that norfluoxetine prevents degeneration of nigrostriatal dopamine neurons in vivo in MPTP-lesioned mice compared to vehicle-treated MPTP-lesioned control mice. MAC-1 immunostaining and hydroethidine histochemical staining showed that norfluoxetine neuroprotection is accompanied by inhibiting MPTP-induced microglial activation and activated microglia-derived reactive oxygen species production in vivo, respectively. In the separate experiments, treatment with norfluoxetine inhibited NADPH oxidase activation and nitrate production in LPS-treated cortical microglial cultures in vitro. Collectively, these in vivo and in vitro results suggest that norfluoxetine could be employed as a novel therapeutic agent for treating PD, which is associated with neuroinflammation and microglia-derived oxidative stress.

scholarly journals Functional validation of a human GLUD2 variant in a murine model of Parkinson’s disease

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Wenlong Zhang ◽  
Junwei Gong ◽  
Liuyan Ding ◽  
Zhiling Zhang ◽  
Xiaowen Pan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neuron ◽  
Tricarboxylic Acid Cycle ◽  
Disease Onset ◽  
Underlying Mechanism ◽  
Related Factor ◽  
Neuron Death

Abstract Parkinson’s disease (PD) is a common neurodegenerative disease characterized by Lewy body formation and progressive dopaminergic neuron death in the substantia nigra (SN). Genetic susceptibility is a strong risk factor for PD. Previously, a rare gain-of-function variant of GLUD2 glutamate dehydrogenase (T1492G) was reported to be associated with early onset in male PD patients; however, the function and underlying mechanism of this variant remains elusive. In the present study, we generated adeno-associated virus expressing GLUD2 and its mutant under the control of the glial fibrillary acidic protein promotor and injected the virus into the SN pars compacta of either untreated mice or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice. Our results demonstrate that GLUD2 mutation in MPTP-induced PD mice exacerbates movement deficits and nigral dopaminergic neuron death and reduces glutamate transporters expression and function. Using GC-Q-TOF/MS-based metabolomics, we determined that GLUD2 mutation damages mitochondrial function by decreasing succinate dehydrogenase activity to impede the tricarboxylic acid cycle in the SN of MPTP-induced PD mice. Accordingly, GLUD2 mutant mice had reduced energy metabolism and increased apoptosis, possibly due to downregulation of brain-derived neurotrophic factor/nuclear factor E2-related factor 2 signaling in in vitro and in vivo PD models. Collectively, our findings verify the function of GLUD2 in PD and unravel a mechanism by which a genetic variant in human GLUD2 may contribute to disease onset.

scholarly journals Loss of SATB1 Induces a p21 Dependent Cellular Senescence Phenotype in Dopaminergic Neurons

2018 ◽  
Author(s):  
Markus Riessland ◽  
Benjamin Kolisnyk ◽  
Tae Wan Kim ◽  
Jia Cheng ◽  
Jason Ni ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cellular Senescence ◽  
Dopaminergic Neurons ◽  
Dna Binding Protein ◽  
Dopamine Neurons ◽  
Human Stem Cell ◽  
Transcriptional Program

AbstractCellular senescence is a mechanism used by mitotic cells to prevent uncontrolled cell division. As senescent cells persist in tissues, they cause local inflammation and are harmful to surrounding cells, contributing to aging. Generally, neurodegenerative diseases, such as Parkinson‘s, are disorders of aging. The contribution of cellular senescence to neurodegeneration is still unclear. SATB1 is a DNA binding protein associated with Parkinson’s disease. We report that SATB1 prevents cellular senescence in post-mitotic dopaminergic neurons. Loss of SATB1 causes activation of a cellular senescence transcriptional program in dopamine neurons, both in human stem cell-derived dopaminergic neurons and in mice. We observed phenotypes which are central to cellular senescence in SATB1 knockout dopamine neurons in vitro and in vivo. Moreover, we found that SATB1 directly represses expression of the pro-senescence factor, p21, in dopaminergic neurons. Our data implicate senescence of dopamine neurons as a contributing factor to the pathology of Parkinson’s disease.

scholarly journals CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Nora Bengoa-Vergniory ◽  
Emilie Faggiani ◽  
Paula Ramos-Gonzalez ◽  
Ecem Kirkiz ◽  
Natalie Connor-Robson ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Investigation ◽  
Induced Pluripotent Stem Cell ◽  
Alpha Synuclein ◽  
Dopamine Neurons ◽  
Molecular Tweezers ◽  
Alpha Synuclein Aggregation

Abstract Parkinson’s disease (PD) affects millions of patients worldwide and is characterized by alpha-synuclein aggregation in dopamine neurons. Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. Here we report that the molecular tweezer CLR01 decreased aggregation and toxicity in induced pluripotent stem cell-derived dopaminergic cultures treated with PD brain protein extracts. In microfluidic devices CLR01 reduced alpha-synuclein aggregation in cell somas when axonal terminals were exposed to alpha-synuclein oligomers. We then tested CLR01 in vivo in a humanized alpha-synuclein overexpressing mouse model; mice treated at 12 months of age when motor defects are mild exhibited an improvement in motor defects and a decreased oligomeric alpha-synuclein burden. Finally, CLR01 reduced alpha-synuclein-associated pathology in mice injected with alpha-synuclein aggregates into the striatum or substantia nigra. Taken together, these results highlight CLR01 as a disease-modifying therapy for PD and support further clinical investigation.

scholarly journals Enhanced Hexokinase 2 Expression and Lactate Production Promote The Apoptosis of Dopaminergic Neurons in Parkinson’s Disease

2021 ◽  
Author(s):  
Jingyi Li ◽  
Longmin Chen ◽  
Qixiong Qin ◽  
Danlei Wang ◽  
Jingwei Zhao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Dopaminergic Neurons ◽  
Lactate Production ◽  
Substantia Nigra Pars Compacta ◽  
Hexokinase 2 ◽  
Lactate Levels

Abstract Background: Parkinson’s disease (PD) is characterized by impaired mitochondrial function and decreased ATP levels. Glycolysis is upregulated and lactate production is enhanced in PD. Since lactate promotes apoptosis and α-synuclein accumulation in neurons, we hypothesized that the increased lactate resulted from upregulated glycolysis is involved in the apoptosis of dopaminergic neurons in PD.Methods: We examined the expression of hexokinase 2 (HK2) and lactate dehydrogenase (LDH), the key enzymes in glycolysis, and lactate levels in the substantia nigra pars compacta (SNpc) of MPTP-induced mouse model of PD and in MPP+-treated SH-SY5Y cells. We investigated the role of HK2, lactate and AMPK pathway in the apoptosis of dopaminergic neurons by intervened with 3-Brpa, the HK2 inhibitor, in in vivo and in vitro systems.Results: We found that the expression of HK2 and LDHA, and lactate levels were markedly increased in brain SNpc of MPTP-treated mouse and in MPP+-treated SH-SY5Y cells. Meanwhile, the apoptosis of dopaminergic neurons in the mouse model and the apoptosis of the SH-SY5Y in vitro system were increased. Intriguingly, using HK2 inhibitor or siRNA can decrease the lactate levels and suppressed the apoptosis of dopaminergic neurons both in vivo and in vitro. Mechanistically, lactate increased the activity of adenosine monophosphate activated protein kinase (AMPK), and suppressed the phosphorylation of serine/threonine kinase 1 (Akt) and mammalian target of rapamycin (mTOR). Conclusion：Inhibition of HK2 ameliorate the apoptosis of dopaminergic neurons through downregulating the lactate production and AMPK/ Akt/ mTOR pathway activation in PD.

scholarly journals The Emerging Role of Neuropeptides in Parkinson’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Yanan Zheng ◽  
Linlin Zhang ◽  
Junxia Xie ◽  
Limin Shi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Age Related ◽  
Pituitary Adenylate Cyclase ◽  
New Strategy

Parkinson’s disease (PD), the second most common age-related neurodegenerative disease, results from the loss of dopamine neurons in the substantia nigra. This disease is characterized by cardinal non-motor and motor symptoms. Several studies have demonstrated that neuropeptides, such as ghrelin, neuropeptide Y, pituitary adenylate cyclase-activating polypeptide, substance P, and neurotensin, are related to the onset of PD. This review mainly describes the changes in these neuropeptides and their receptors in the substantia nigra-striatum system as well as the other PD-related brain regions. Based on several in vitro and in vivo studies, most neuropeptides play a significant neuroprotective role in PD by preventing caspase-3 activation, decreasing mitochondrial-related oxidative stress, increasing mitochondrial biogenesis, inhibiting microglial activation, and anti-autophagic activity. Thus, neuropeptides may provide a new strategy for PD therapy.

scholarly journals Disulfide bridge formation prevents CaMKII/Calmodulin interaction in Parkinson’s disease

2020 ◽  
Author(s):  
Roberto Di Maio ◽  
Ignacio J. General ◽  
Emily Furbee ◽  
Joseph C. Ayoob ◽  
Sandra L. Castro ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Regulatory Protein ◽  
Disulfide Bridge ◽  
Dopamine Neurons ◽  
Independent Manner ◽  
Bridge Formation ◽  
Methionine Residues

AbstractThere is increasing evidence for disordered Ca2+ signaling in dopamine neurons in Parkinson’s disease (PD), and this likely involves altered Ca2+/calmodulin-dependent protein kinase II (CaMKII) function. Previous work suggests that oxidative stress - a major feature in PD pathogenesis - affects regulatory methionine residues that sustain CaMKII activity in a Ca2+/CaM-independent manner. Here, applying computational modeling, we predicted formation of a defined disulfide bridge close to the CaMKII docking site for Ca2+/CaM binding. In vitro and in vivo investigations using PD models revealed formation of a disulfide bridge and loss of the CaMKII–calmodulin interaction. Mutagenesis of the relevant cysteine residues abrogated disulfide bridge formation and recovered the CaMKII–calmodulin interaction. Importantly, dopamine neurons from post-mortem PD brain specimens also lost this regulatory protein-protein interaction, providing relevance in the human disease. This study provides novel insights into oxidative CaMKII-CaM dysfunction, which may contribute to the pathophysiology of PD.

scholarly journals Calcitriol Alleviates MPP+- and MPTP-Induced Parthanatos Through the VDR/PARP1 Pathway in the Model of Parkinson’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Junjie Hu ◽  
Jiawei Wu ◽  
Fang Wan ◽  
Liang Kou ◽  
Sijia Yin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Vitamin D ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Cell Model ◽  
Dopamine Neurons ◽  
Protective Effects ◽  
Excessive Activation

The pathogenesis of Parkinson’s disease (PD) is currently unclear. Recent studies have suggested a correlation between vitamin D and PD. Vitamin D and its analogs have protective effects in animal models of PD, but these studies have not clarified the mechanism. Parthanatos is a distinct type of cell death caused by excessive activation of poly (ADP-ribose) polymerase-1 (PARP1), and the activation of PARP1 in PD models suggests that parthanatos may exist in PD pathophysiology. 1,25-Dihydroxyvitamin D3 (calcitriol) is a potential inhibitor of PARP1 in macrophages. This study aimed to investigate whether calcitriol treatment improves PD models and its effects on the parthanatos pathway. A 1-methyl-4-phenylpyridinium (MPP+)-induced cell model and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) subacute animal model were selected as the in vitro and in vivo PD models, and calcitriol was applied in these models. Results showed that parthanatos existed in the MPP+-induced cell model and pretreatment with calcitriol improved cell viability, reduced the excessive activation of PARP1, and relieved parthanatos. The application of calcitriol in the MPTP subacute animal model also improved behavioral tests, restored the damage to dopamine neurons, and reduced the activation of PARP1-related signaling pathways. To verify whether calcitriol interacts with PARP1 through its vitamin D receptor (VDR), siRNA, and overexpression plasmids were used to downregulate or overexpress VDR. Following the downregulation of VDR, the expression and activation of PARP1 increased and PARP1 was inhibited when VDR was overexpressed. Coimmunoprecipitation verified the combination of VDR and PARP1. In short, calcitriol can substantially improve parthanatos in the MPP+-induced cell model and MPTP model, and the protective effect might be partly through the VDR/PARP1 pathway, which provides a new possibility for the treatment of PD.

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.

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