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Thioredoxin-Interacting Protein(TXNIP) Regulates Parkin/PINK1-mediated Mitophagy in Dopaminergic Neurons Under High-glucose Conditions: Implications for Molecular Links Between Parkinson’s Disease and Diabetes

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Neuroscience Bulletin 2020年第4期36卷 346-358页

作者： Cun-Jin su Zhu shen Ru-Xiao Cui Ya Huang De-Lai Xu Feng-Lun Zhao Jie Pan Ai-Ming shi Tong Liu Yun-Li Yu Department of Pharmacy The Second Affiliated Hospital of Soochow UniversitySuzhou 215004China Institute of Neuroscience Soochow UniversitySuzhou 215004China Department of Clinical Pharmacology The Second Affiliated Hospital of Soochow UniversitySuzhou 215004China

Patients with diabetes mellitus have a higher risk of developing Parkinson’s disease(PD). However, the molecular links between PD and diabetes remain unclear.In this study, we investigated the roles of thioredoxininteracting protein(TXNIP) in Parkin/PINK1-mediated mitophagy in dopaminergic(DA) cells under high-glucose(HG) conditions. In streptozotocin-induced diabetic mice,TXNIP was upregulated and autophagy was inhibited in the midbrain, while the loss of DA neurons was accelerated by hyperglycemia. In cultured PC12 cells under HG, TXNIP expression was upregulated and the intracellular reactive oxygen species(ROs) levels increased, leading to cell death. Autophagic flux was further blocked and PINK1 expression was decreased under HG conditions. Parkin expression in the mitochondrial fraction and carbonyl cyanide 3-chlorophenylhydrazone(CCCP)-induced co-localization of COX IV(marker for mitochondria) and LAMP1(marker for lysosomes) were also significantly decreased by HG. Overexpression of TXNIP was sufficient to decrease the expression of both PINK1 and Parkin in PC12 cells, while knockdown of the expression of TXNIP by si RNA decreased intracellular ROs and attenuated cellular injury under HG. Moreover, inhibition of TXNIP improved the CCCP-induced co-localization of COX IV and LAMP1 in PC12 cells under HG. Together, these results suggest that TXNIP regulates Parkin/PINK1-mediated mitophagy under HG conditions, and targeting TXNIP may be a promising therapeutic strategy for reducing the risk of PD under hyperglycemic conditions.

关键词： Diabetes mellitus Parkinson’s disease High glucose TXNIP Mitophagy PC12 cells

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Effect of stromal cell-derived factor-1/CXCR4 axis in neural stem cell transplantation for Parkinson’s disease

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Neural Regeneration Research 2020年第1期15卷 112-119页

作者： Jiao-Tian Xu Yuan Qian Wei Wang Xiao-Xiang Chen Yang Li Yu Li Zhi-Yong Yang Xiao-Bin song Di Lu Xing-Li Deng Department of Neurosurgery First Affiliated Hospital of Kunming Medical UniversityKunmingYunnan ProvinceChina Diagnosis Prenatal Unit Department of ObstetricsFirst Affiliated Hospital of Kunming Medical UniversityKunmingYunnan ProvinceChina The People’s Hospital of Chuxiong Yi Autonomous Prefecture ChuxiongYunnan ProvinceChina Rehabilitation Engineering Research Laboratory Biomedicine Engineering Research CenterKunming Medical UniversityKunmingYunnan ProvinceChina

Previous studies have shown that neural stem cell transplantation has the potential to treat Parkinson’s disease,but its specific mechanism of action is still unclear.stromal cell-derived factor-1 and its receptor,chemokine receptor 4(CXCR4),are important regulators of cell migration.We speculated that the CXCR4/stromal cell-derived factor 1 axis may be involved in the therapeutic effect of neural stem cell transplantation in the treatment of Parkinson’s disease.A Parkinson’s disease rat model was injected with 6-hydroxydopamine via the right ascending nigrostriatal dopaminergic pathway,and then treated with 5μL of neural stem cell suspension(1.5×104/L)in the right substantia nigra.Rats were intraperitoneally injected once daily for 3 days with 1.25 mL/kg of the CXCR4 antagonist AMD3100 to observe changes after neural stem cell transplantation.parkinson-like behavior in rats was detected using apomorphine-induced rotation.Immunofluorescence staining was used to determine the immunoreactivity of tyrosine hydroxylase,CXCR4,and stromal cell-derived factor-1 in the brain.Using quantitative real-time polymerase chain reaction,the mRNA expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra were measured.In addition,western blot assays were performed to analyze the protein expression of stromal cell-derived factor-1 and CXCR4.Our results demonstrated that neural stem cell transplantation noticeably reduced apomorphine-induced rotation,increased the mRNA and protein expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra,and enhanced the immunoreactivity of tyrosine hydroxylase,CXCR4,and stromal cell-derived factor-1 in the brain.Injection of AMD3100 inhibited the aforementioned effects.These findings suggest that the stromal cell-derived factor-1/CXCR4 axis may play a significant role in the therapeutic effect of neural stem cell transplantation in a rat model of Parkinson’s disease.This study was approved by the Animal Care and Use Committee of Kunming Medical Un

关键词： AMD3100 corpus striatum CXCR4 neural stem cells Parkinson’s disease stromal cell-derived factor-1 substantia nigra

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Replacing what’s lost: a new era of stem cell therapy for Parkinson’s disease

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Translational Neurodegeneration 2020年第1期9卷 10-19页

作者： Yong Fan Winanto shi-Yan Ng The Third Affiliated Hospital of Guangzhou Medical University Guangzhou 510150China Institute of Molecular and Cell Biology A^*STAR Research EntitiesSingapore 138673Singapore Yong Loo Lin school of Medicine(Physiology) National University of SingaporeSingapore 117456Singapore National Neuroscience Institute Singapore 308433Singapore

Background stem cells hold tremendous promise for regenerative medicine because they can be expanded infinitely,giving rise to large numbers of differentiated cells required for transplantation.stem cells can be derived from fetal sources,embryonic origins(embryonic stem cells or EsCs)or reprogrammed from adult cell types(induced pluripotent stem cells or iPsCs).One unique property of stem cells is their ability to be directed towards specific cell types of clinical interest,and can mature into functional cell types in vivo.While transplantations of fetal or EsC-derived tissues are known to illicit a host immunogenic response,autologous transplantations using cell types derived from one’s own iPsCs eliminate risks of tissue rejection and reduce the need for immunosuppressants.However,even with these benefits,cell therapy comes with significant hurdles that researchers are starting to overcome.In this review,we will discuss the various steps to ensure safety,efficacy and clinical practicality of cell replacement therapy in neurodegenerative diseases,in particular,Parkinson’s disease.Main body Parkinson’s disease(PD)results from a loss of dopaminergic neurons from the substantia nigra and is an ideal target for cell replacement therapy.Early trials using fetal midbrain material in the late 1980s have resulted in long term benefit for some patients,but there were multiple shortcomings including the non-standardization and quality control of the transplanted fetal material,and graft-induced dyskinesia that some patients experience as a result.On the other hand,pluripotent stem cells such as EsCs and iPsCs serve as an attractive source of cells because they can be indefinitely cultured and is an unlimited source of cells.stem cell technologies and our understanding of the developmental potential of EsCs and iPsCs have deepened in recent years and a clinical trial for iPsC-derived dopaminergic cells is currently undergoing for PD patients in Japan.In this focused review,we will first provide a historical aspect of cell

关键词： Parkinson’s disease Induced pluripotent stem cells Cell therapy Regenerative medicine

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Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study

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Translational Neurodegeneration 2020年第1期9卷 96-104页

作者： Heinz Reichmann Andrew Lees José-Francisco Rocha Diogo Magalhaes Patrício soares-da-silva the OPTIPARK investigators Department of Neurology University of DresdenDresdenGermany University College London Reta Lila Weston InstituteLondonUK Global Parkinson’s Disease Department BIAL–Portela&CA S.ACoronadoPortugal Research and Development Department BIAL–Portela&CA S.Ada Siderurgia Nacional4745-457 S Mamede do CoronadoPortugal Department of Pharmacology and Therapeutics Faculty of MedicineUniversity PortoPortoPortugal MedInUP Center for Drug Discovery and Innovative MedicinesUniversity PortoPortoPortugal 不详

Background:The efficacy and safety of opicapone,a once-daily catechol-O-methyltransferase inhibitor,have been established in two large randomized,placebo-controlled,multinational pivotal trials.still,clinical evidence from routine practice is needed to complement the data from the pivotal trials.Methods:OPTIPARK(NCT02847442)was a prospective,open-label,single-arm trial conducted in Germany and the UK under clinical practice conditions.Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3(Germany)or 6(UK)months in addition to their current levodopa and other antiparkinsonian treatments.The primary endpoint was the Clinician’s Global Impression of Change(CGI-C)after 3 months.secondary assessments included Patient Global Impressions of Change(PGI-C),the Unified Parkinson’s Disease Rating scale(UPDRs),Parkinson’s Disease Questionnaire(PDQ-8),and the Non-Motor symptoms scale(NMss).safety assessments included evaluation of treatment-emergent adverse events(TEAEs)and serious adverse events(sAEs).Results:Of the 506 patients enrolled,495(97.8%)took at least one dose of opicapone.Of these,393(79.4%)patients completed 3 months of treatment.Overall,71.3 and 76.9%of patients experienced any improvement on CGI-C and PGI-C after 3 months,respectively(full analysis set).At 6 months,for UK subgroup only(n=95),85.3%of patients were judged by investigators as improved since commencing treatment.UPDRs scores at 3 months showed statistically significant improvements in activities of daily living during OFF(mean±sD change from baseline:?3.0±4.6,pscores during ON(?4.6±8.1,psD improvements of?3.4±12.8 points for PDQ-8 and-6.8±19.7 points for NMss were statistically significant versus baseline(both pst of TEAEs(94.8%of events)were of mild or moderate intensity.TEAEs considered to be at least possibly related to opicapone were reported for 45.1%of patients,with dyskinesia(11.5%)and dry mouth(6.5%)being the most frequently reported.serious TEAEs consi

关键词： Levodopa Motor fluctuations Open-label Opicapone Parkinson’s disease

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Emotion processing in parkinson's disease: a blood oxygenation level-dependent functional magnetic resonance imaging study

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Neural Regeneration Research 2019年第4期14卷 666-672页

作者： Mohammed Benzagmout sa?d Boujraf Badreeddine Alami Hassane Ali Amadou Halima El Hamdaoui Amine Bennani Mounir Jaafari Ismail Rammouz Mustapha Maaroufi Rabia Magoul Driss Boussaoud Laboratory of Clinical Neuroscience Faculty of Medicine Department of Neurosurgery University Hospital of Fez Laboratory of Neuroendocrinology and Nutritional and Climatic Environment Faculty of Sciences Dhar El Mahraz Department of Biophysics and Clinical MRI Methods Faculty of Medicine Department of Radiology and Clinical Imaging University Hospital of Fez Department of Psychiatry University Hospital of Fez Aix Marseille Université INSERM INS Institut de Neurosciences des Systèmes

parkinson's disease is a neurodegenerative disorder caused by loss of dopamine neurons in the substantia nigra pars compacta. Tremor, rigidity, and bradykinesia are the major symptoms of the disease. These motor impairments are often accompanied by affective and emotional dysfunctions which have been largely studied over the last decade. The aim of this study was to investigate emotional processing organization in the brain of patients with parkinson's disease and to explore whether there are differences between recognition of different types of emotions in parkinson's disease. We examined 18 patients with parkinson's disease(8 men, 10 women) with no history of neurological or psychiatric comorbidities. All these patients underwent identical brain blood oxygenation level-dependent functional magnetic resonance imaging for emotion evaluation. Blood oxygenation level-dependent functional magnetic resonance imaging results revealed that the occipito-temporal cortices, insula, orbitofrontal cortex, basal ganglia, and parietal cortex which are involved in emotion processing, were activated during the functional control. Additionally, positive emotions activate larger volumes of the same anatomical entities than neutral and negative emotions. Results also revealed that parkinson's disease associated with emotional disorders are increasingly recognized as disabling as classic motor symptoms. These findings help clinical physicians to recognize the emotional dysfunction of patients with parkinson's disease.

关键词： Parkinson’s disease emotion processing Blood oxygenation level-dependent functional magnetic resonance imaging brain activation dopamine neural regeneration

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Using induced pluripotent stem cells for modeling Parkinson’s disease

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World Journal of stem Cells 2019年第9期11卷 634-649页

作者： Minjing Ke Cheong-Meng Chong Huanxing su state Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macao

Parkinson’s disease(PD)is an age-related neurodegenerative disease caused by the progressive loss of dopaminergic(DA)neurons in the substantia nigra.As DA neurons degenerate,PD patients gradually lose their ability of movement.To date no effective therapies are available for the treatment of PD and its pathogenesis remains unknown.Experimental models that appropriately mimic the development of PD are certainly needed for gaining mechanistic insights into PD pathogenesis and identifying new therapeutic targets.Human induced pluripotent stem cells(iPsCs)could provide a promising model for fundamental research and drug screening.In this review,we summarize various iPsCs-based PD models either derived from PD patients through reprogramming technology or established by gene-editing technology,and the promising application of iPsC-based PD models for mechanistic studies and drug testing.

关键词： Parkinson’s disease Dopaminergic neurons Induced pluripotent stem cells somatic cell reprogramming Aging

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Challenges and trends in apomorphine drug delivery systems for the treatment of parkinson's disease

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Asian Journal of Pharmaceutical sciences 2018年第6期13卷 507-517页

作者： Nrupa Borkar Huiling Mu René Holm Department of Pharmacy Faculty of Health and Medical Sciences University of Copenhagen Drug Product Development Janssen Research and Development Johnson & Johnson

parkinson's disease(PD) is a chronic debilitating disease affecting approximately 1% of the population over the age of 60. The severity of PD is correlated to the degree of dopaminergic neuronal loss. Apomorphine has a similar chemical structure as the neurotransmitter dopamine and has been used for the treatment of advanced PD patients. In PD patients,apomorphine is normally administered subcutaneously with frequent injections because of the compound's extensive hepatic first-pass metabolism. There is, hence, a large unmet need for alternative administrative routes for apomorphine to improve patient compliance.The present review focuses on the research and development of alternative delivery of apomorphine, aiming to highlight the potential of non-invasive apomorphine therapy in PD,such as sublingual delivery and transdermal delivery.

关键词： Apomorphine Drug delivery Parkinson’s disease Alternative apomorphine therapy Non-invasive delivery Excipients

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parkinson's Disease Risk Variant rs1109303 Regulates the Expression of INPP5K and CRK in Human Brain

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Neuroscience Bulletin 2019年第2期35卷 365-368页

作者： Guiyou Liu Yi Zhao Jing-yi sun Bao-liang sun Key Laboratory of Cerebral Microcirculation in Universities of shandong Department of Neurology Affiliated Hospital of Taishan Medical College school of Life science and Technology Harbin Institute of Technology Affiliated Hospital Taishan Medical University Wonju severance Christian Hospital Wonju College of Medicine Yonsei University

Dear Editor,Parkinson’s disease (PD) is the second most common neurodegenerative disease in the elderly (1, 2)PD affects1%–2%of the world’s population older than 65 years(3–5)In recent years, large-scale genome-wide association studies (GWAs) have been widely conducted to identify the common genetic risk genes for PD. A number of PD susceptibility genes have been identified, including sNCA,MAPT, NUCKs1, the HLA region, GAK, BsT1, GBA,WNT3, RIT2, and LRRK2 [3–5].

关键词： Parkinson’s Disease QTL sLC

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Influence of simvastatin on dopaminergic neurons of lipopolysaccharide—induced rat model of parkinson's disease

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Asian Pacific Journal of Tropical Medicine 2015年第1期8卷 64-67页

作者： Tan Wang Xue-Bin Cao Xiao-Wu Chen Pei-Pei Huang Tian Zhang Zhi-Bin Chen Bei-sha Tang Department of Neurology Xiangya HospitalCentral South University Department of Neurology Affiliated Hospital of Hainan Medical College Department of Neurology Union HospitalTongji Medical CollegeHuazhong University of Science and Technology

Objective::To investigate the neuroprotective effects of simvastatin on lipopolysaccharide(LPs)-indueed rat model of parkinson's disease(PD) and the mechanisms involved.Methods:Hemiparkinsonian rat models were induced by stereotaxieal injection of LPs in the right substantia nigra compacts.After 2 weeks of simvastatin treatment,rotational behavior test was performed after the intraperitoneal injection of apomorphine.Expression of tyroxine hydroxylase(TH) and glial fibrillan acidic protein were analyzed through immunohistochemical staining of substantia nigra and striatum,and the level of TNF-α was evaluated using enzyme-linked immunosorbent assay.Results:Comparing with untreated group,behavioral symptoms of the rats were significantly less in the rats that received simvastatin treatment.The TH positive cell count in substantia nigra and striatum were significantly increased(Pssion was significantly decreased(Psimvastatin group compared to untreated group.Conclusions:simvastatin could effectively inhibit the activation of astrocytes,reduce TNF-α expression,and exert anti-inflammatory effects,and thus protect the dopaminergic neurons in substantia nigra and striatum of the rat model of PD.

关键词： Parkinson’s disease simvastatin Lipopolysaccharide astrocyte Tumor necrosis factor-alpha

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Co-transplantation of macaque autologous schwann cells and human embryonic nerve stem cells in treatment of macaque parkinson's disease

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Asian Pacific Journal of Tropical Medicine 2012年第1期5卷 7-14页

作者： Ying Xia Chengchuan Jiang Zuowei Cao Keshan shi Yang Wang Department of Neurosurgery Haikou HospitalXiangya Medical SchoolCentral South University Department of Neurosurgery Huashan HospitalFudan University Department of Neurosurgery Haikou HospitalXiangya Medical SchoolCentral South Unirersity Department of Anatomy Histology and EmbryologyShanghai Medical CenterFudan University

Objective:To investigate the therapeutic effects of co-transplantation with schwann cells（sCs） and human embryonic nerve stem cells（NsCs） on macaque Parkinson’s disease（PD）.Methods: Macaque autologous sCs and human embryonic NsCs were adopled for the treatment of macaque PD.Results:six months after transplantation,positron emission computerized tomography showed that sup>18sup>F-FP-β-CIT was significantly concentrated in the injured striatum in the cotransplanted group.Immunohistoehemieal staining of transplanted area tissue showed migration of tyrosine hydroxylase positive cells from the transplant area to the surrounding area was significantly increased in the co-transplanted group.Conclusions:Co-transplantation of sCs and NsCs could effectively cure PD in macaques.sCs harvested from the autologous peripheral nerves can avoid rejection and the ethics problems,so it is expected to be applied clinically.

关键词： schwann cells Nerve stem cells Parkinson’s disease Co-transplantation Macaque

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