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Biomarkers for Parkinson’s Disease: How Good Are They?

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Neuroscience Bulletin 2020年第2期36卷 183-194页

作者： Tianbai Li Weidong Le Center for Clinical Research on Neurological diseases the First Affiliated HospitalDalian Medical UniversityDalian 116021China liaoning Provincial key laboratory for Research on the Pathogenic Mechanisms of Neurological diseases the First Affiliated HospitalDalian Medical UniversityDalian 116021China

Parkinson’s disease(PD)is a complex neurodegenerative disorder with no cure in *** challenges of the disease include the inability to make a definitive diagnosis at the early stages and difficulties in predicting the disease *** unmet demand to identify reliable biomarkers for early diagnosis and management of the disease course of PD has attracted a lot of ***,only a few reported candidate biomarkers have been tried in clinical practice at the present *** on PD biomarkers have often overemphasized the discovery of novel identity,whereas efforts to further evaluate such candidates are ***,we update the new development of biomarker discovery in PD and discuss the standard process in the evaluation and assessment of the diagnostic or prognostic value of the identified potential PD biomarkers in this review *** developments in combined biomarkers and the current status of clinical trials of biomarkers as outcome measures are also *** believe that the combination of different biomarkers might enhance the specificity and sensitivity over a single measure that might not be sufficient for such a multiplex disease.

关键词： Parkinson’s disease Biomarkers Combined biomarkers Clinical trials

Interplay between the glymphatic system and neurotoxic proteins in Parkinson’s disease and related disorders:current knowledge and future directions

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Neural Regeneration Research 2024年第9期19卷 1973-1980页

作者： Yumei Yue Xiaodan Zhang Wen Lv Hsin-Yi Lai Ting Shen department of Neurology of Sir Run Run Shaw Hospital Zhejiang University School of MedicineZhejiang UniversityHangzhouZhejiang ProvinceChina department of Emergency Medicine The University of Hong KongHong Kong Special Administrative RegionChina department of Neurology of the Second Affiliated Hospital and School of Brain Science and Brain Medicine Interdisciplinary Institute of Neuroscience and TechnologyKey Laboratory of Medical Neurobiology of Zhejiang ProvinceZhejiang University School of MedicineHangzhouZhejiang ProvinceChina College of Biomedical Engineering and Instrument Science Zhejiang UniversityHangzhouZhejiang ProvinceChina MOE Frontier Science Center for Brain Science and Brain-Machine Integration State Key Laboratory of Brain-machine IntelligenceSchool of Brain Science and Brain MedicineZhejiang UniversityHangzhouZhejiang ProvinceChina

Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired elimination of these neurotoxic *** parkinsonism,which has the same clinical presentation and neuropathology as Parkinson’s disease,expands the disease landscape within the continuum of Parkinson’s disease and related *** glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial *** of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease,as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal ***,impairment of the glymphatic system could be considered as the final common pathway to *** evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders;however,many unanswered questions *** review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related *** focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins,including loss of polarization of aquaporin-4 in astrocytic endfeet,sleep and circadian rhythms,neuroinflammation,astrogliosis,and *** review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders,and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.

关键词： atypical parkinsonism glymphatic system magnetic resonance imaging neurotoxic proteins Parkinson’s disease

Effects of triptolide on hippocampal microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer＇s disease

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Neural Regeneration Research 2016年第9期11卷 1492-1498页

作者： Jian-ming Li Yan Zhang Liang Tang Yong-heng Chen Qian Gao Mei-hua Bao Ju Xiang De-liang Lei department of Neurology Xiangya Hospital Central South University Changsha Hunan Province China department of Anatomy and neurobiology Central South University School of Basic Medical Science Changsha Hunan Province China Neuroscience Research Center Changsha Medical University ChangshaHunan Province China department of Anatomy Changsha Medical University Changsha Hunan Province China

The principal pathology of Alzheimer＇s disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile pl aques, which in turn induce neuroinflammation in the brain. Triptolide, a natural extract from the vine-like herb Tripterygium wilfordii Hook F, has potent anti-inflammatory and immunosuppressive efficacy. Therefore, we determined if triptolide can inhibit activation and proliferation of microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer＇s disease. We used 1 or 5 μg/kg/d triptolide to treat APP/PS1 double transgenic mice （aged 4-4.5 months） for 45 days. Unbiased stereology analysis found that triptolide dose-dependent- ly reduced the total number of microglial cells, and transformed microglial cells into the resting state. Further, triptolide （5 μg/kg/d） also reduced the total number of hippocampal astrocytes. Our in vivo test results indicate that triptolide suppresses activation and proliferation of microglial cells and astrocytes in the hippocampus of APP/PS 1 double transgenic mice with Alzheimer＇s disease.

关键词： nerve regeneration neurodegenerative disease traditional Chinese medicine Tripterygium wilfordii Hook F triptolide Alzheimer'sdisease amyloid plaques amyloid-β amyloid precursor protein inflammation microglia astrocytes neural regeneration

Mitophagy in neurodegenerative disease pathogenesis

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Neural Regeneration Research 2024年第5期19卷 998-1005页

作者： Kan Yang Yuqing Yan Anni Yu Ru Zhang Yuefang Zhang Zilong Qiu Zhengyi Li Qianlong Zhang Shihao Wu Fei Li department of Developmental and Behavioural Pediatric&Child Primary Care Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children’s Environmental HealthXinhua HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Center for Excellence in Brain Science and Intelligence Technology Institute of NeuroscienceState Key Laboratory of NeuroscienceCAS Key Laboratory of Primate NeurobiologyChinese Academy of SciencesShanghaiChina College of Materials and Chemical Engineering Hunan Institute of EngineeringXiangtanHunan ProvinceChina School of Medicine Yunnan UniversityKunmingYunnan ProvinceChina Songjiang Research Institute Shanghai Jiao Tong University School of MedicineShanghaiChina Neurosurgery department Kunming Yenan HospitalKunmingYunnan ProvinceChina

Mitochondria are critical cellular energy resources and are central to the life of the *** selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and *** neurons are postmitotic and consume substantial energy,thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional *** evidence indicates that mitophagy is pivotal to the pathogenesis of neurological ***,more work is needed to study mitophagy pathway components as potential therapeutic *** this review,we briefly discuss the characteristics of nonselective autophagy and selective autophagy,including ERphagy,aggrephagy,and *** then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological ***,we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate ***,we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral ***,we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative ***,our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.

关键词： Alzheimer’s disease amyotrophic lateral sclerosis autophagy mitochondria mitophagy mitophagy receptor Parkin Parkinson’s disease PINK1

Single-cell brain atlas of Parkinson's disease mouse model

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Journal of Genetics and Genomics 2021年第4期48卷 277-288页

作者： Jixing Zhong Gen Tang Jiacheng Zhu Weiying Wu Ge Li Xiumei Lin Langchao Liang Chaochao Chai Yuying Zeng Feiyue Wang Lihua Luo Jiankang Li Fang Chen Zhen Huang Xiuqing Zhang Yu Zhang Hongde Liu Xin Qiu Shengping Tang Dongsheng Chen School of Biological Science&Medical Engineering Southeast UniversityNanjing 210096China BGI-Shenzhen Shenzhen 518083China Shenzhen Children's Hospital Shenzhen 518083China BGI Education Center University of Chinese Academy of SciencesShenzhen 518083China department of neurobiology NHC and CAMS Key Laboratory of Medical NeurobiologySchool of Brain Science and Brian MedicineAnd the MOE Frontier Science Center for Brain Research and Brain-Machine IntegrationZhejiang University School of MedicineHangzhou 310012China Guangdong Provincial key laboratory of laboratory Animals Guangdong Laboratory Animals Monitoring InstituteGuangzhouGuangdong 510663China MGI BGI-ShenzhenShenzhen 518083China Life Science College Fujian Normal UniversityFuzhou 350108China key laboratory of Special Marine Bio-resources Sustainable Utilization of Fujian province Fuzhou 350108China

Parkinson's disease(PD)is a neurodegenerative disease,leading to the impairment of movement *** pathogenesis has been largely investigated,either limited to bulk transcriptomic levels or at certain cell types,which failed to capture the cellular heterogeneity and intrinsic interplays among distinct cell ***,we report the application of single-nucleus RNA-seq on midbrain,striatum,and cerebellum of theα-syn-A53 T mouse,a well-established PD mouse model,and matched controls,generating the first single cell transcriptomic atlas for the PD model mouse brain composed of 46,174 individual ***,we comprehensively depicte the dysfunctions in PD pathology,covering the elevation of NF-k B activity,the alteration of ion channel components,the perturbation of protein homeostasis network,and the dysregulation of glutamatergic ***,we identify a variety of cell types closely associated with PD risk *** together,our study provides valuable resources to systematically dissect the molecular mechanism of PD pathogenesis at the single-cell resolution,which facilitates the development of novel approaches for diagnosis and therapies against PD.

关键词： Parkinson’s disease α-syn-A53T Single-nucleus RNA-Seq Pathogenesis Neuroinflammtion

Uncarialins J-M from Uncaria rhynchophylla and Their Anti-depression Mechanism in Unpredictable Chronic Mild Stress-Induced Mice via Activating 5-HT_(1A) Receptor

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Chinese Journal of Chemistry 2021年第5期39卷 1331-1343页

作者： Zhen-Long Yu Rong Bai Jun-Jun Zhou Hui-Lian Huang Wen-Yu Zhao Xiao-Kui Huo Ya-Hui Yang Zhi-Lin Luan Bao-Jing Zhang Cheng-Peng Sun Xiao-Chi Ma Dalian key laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention National&Local Joint Engineering Research Center for Drug Development of Neurodegenerative DiseaseCollege of PharmacyCollege(Institute)of Integrative MedicineDalian Medical UniversityDalianLiaoning 116044China department of Pharmacy Shanghai East HospitalTongji UniversityShanghai 200120China laboratory of Modern Preparation of Traditional Chinese Medicine Ministry of EducationJiangxi University of Traditional Chinese MedicineNanchangJiangxi 330103China

Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long *** investigation of ***,eleven monoterpene indole alkaloids,including four new compounds uncarialins J-M(1-4)and seven known analogues(5-11),were isolated and *** structural characterization was conducted using HRESIMS,1D and 2D NMR,electronic circular dichroism(ECD)spectra,and quantum chemical *** 1,2,7,and 9-11 displayed significant ag-onistic effects towards 5-HT_(1A) receptor,and their EC_(50) values were 7.86,732,2.24,1.18,1.52,and 3.75μmol/L,***,in vivo experimental results fully revealed that hirsuteine(7)displayed a significant antidepression effect in unpredictable chronic mild stress(UCMS)-induced depression mice mainly via regulating 5-HT_(1A) signaling *** docking and site-directed amino acid mutation verified that amino acid residues Aspll6 and Asn386 were the binding sites of hirsuteine(7)with 5-HT_(1A) *** addition,pre-treatment of mice with WAY 100635 also blocked the anti-depression effect of hirsuteine(7),which further demonstrated that 5-HT_(1A) receptor was a potential target of hirsuteine(7)to effectively treat *** findings indicated the therapeutic material basis of *** and the anti-depression underlying mechanism of hirsuteine(7),and further provided the useful guidance for the development of hirsuteine(7)as a potential antidepressant candidate.

关键词： Monoterpene indole alkaloids Hirsuteine Depression 5-HT_(1A)receptor Site-directed amino acid mutation

Clinic, neuropathology and molecular genetics of frontotemporal dementia: a mini-review

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Translational Neurodegeneration 2013年第1期2卷 43-51页

作者： Xiao-dong Pan Xiao-chun Chen department of Neurology Union Hospital of Fujian Medical University29 Xinquan RoadFuzhou 350001China key laboratory of Brain Aging and neurodegenerative Disease Fujian Institute of GeriatricsUnion Hospital of Fujian Medical University29 XinquanRoadFuzhou 350001China Centre of neurobiology Fujian Medical University88 Jiaotong RoadFuzhou 350001China

Frontotemporal lobar degeneration(FTLD)represents a group of clinically,neuropathologically and genetically heterogeneous disorders with plenty of overlaps between the neurodegenerative mechanism and the clinical *** is pathologically characterized by the frontal and temporal lobar *** dementia(FTD)clinically presents with abnormalities of behavior and personality and language impairments *** clinical spectrum of FTD encompasses distinct canonical syndromes:behavioural variant of FTD(bvFTD)and primary progressive *** later includes nonfluent/agrammatic variant PPA(nfvPPA or PNFA),semantic variant PPA(svPPA or SD)and logopenic variant PPA(lvPPA).In addition,there is also overlap of FTD with motor neuron disease(FTD-MND or FTD-ALS),as well as the parkinsonian syndromes,progressive supranuclear palsy(PSP)and corticobasal syndrome(CBS).The FTLD spectrum disorders are based upon the predominant neuropathological proteins(containing inclusions of hyperphosphorylated tau or ubiquitin protein,e.g transactive response(TAR)DNA-binding protein 43 kDa(TDP-43)and fusedin-sarcoma protein in neurons and glial cells)into three main categories:(1)microtubule-associated protein tau(FTLD-Tau);(2)TAR DNA-binding protein-43(FTLD-TDP);and(3)fused in sarcoma protein(FTLD-FUS).There are five main genes mutations leading clinical and pathological variants in FTLD that identified by molecular genetic studies,which are chromosome 9 open reading frame 72(C9ORF72)gene,granulin(GRN)gene,microtubule associated protein tau gene(MAPT),the gene encoding valosin-containing protein(VCP)and the charged multivesicular body protein 2B(CHMP2B).In this review,recent advances on the different clinic variants,neuroimaging,genetics,pathological subtypes and clinicopathological associations of FTD will be discussed.

关键词： bvFTD Nonfluent/agrammatic variant Semantic variant Logopenic variant Molecular genetics MAPT GRN C9ORF72

Targeting β-secretase with RNAi in neural stem cells for Alzheimer's disease therapy

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Neural Regeneration Research 2013年第33期8卷 3095-3106页

作者： Zhonghua Liu Shengliang Li Zibin Liang Yan Zhao Yulin Zhang Yaqi Yang Minjuan Wang Feng Li department of neurobiology and Anatomy Zhongshan School of MedicineSun Yat-sen University

There are several major pathological changes in Alzheimer＇s disease, including apoptosis of cho- linergic neurons, overactivity or overexpression of 13-site amyloid precursor protein cleaving enzyme 1 （BACE1） and inflammation. In this study, we synthesized a 19-nt oligonucleotide targeting BACE1, the key enzyme in amyloid beta protein （AI3） production, and introduced it into the pSilenCircle vector to construct a short hairpin （shRNA） expression plasmid against the BACE1 gene. We transfected this vector into C17.2 neural stem cells and primary neural stem cells, resulting in downregulation of the BACE1 gene, which in turn induced a considerable reduction in reducing AI3 protein production. We anticipate that this technique combining cell transplantation and gene ther- apy will open up novel therapeutic avenues for Alzheimer＇s disease, particularly because it can be used to simultaneously target several pathogenetic changes in the disease.

关键词： neural regeneration neurodegenerative disease secretase neural stem cells Alzheimer'sdisease C17.2 neural stem cells primary neural stem cells shRNA plasmid genetic modification grants-supported paper neuroregeneration

Effect of Apolipoprotein E Genotypes on Huntington’s Disease Phenotypes in a Han Chinese Population

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Neuroscience Bulletin 2019年第4期35卷 756-762页

作者： Xiao-Yan Li Yan-Bin Zhang Miao Xu Hong-Rong Cheng Yi Dong Wang Ni Hong-Lei Li Zhi-Ying Wu department of Neurology and Research Center of Neurology in the Second Affiliated Hospital and Key Laboratory of Medical Neurobiology of Zhejiang Province Zhejiang University School of Medicine Hangzhou 310009 China department of Neurology and Institute of Neurology First Affiliated Hospital Fujian Medical University Fuzhou 350005 China department of Neurology and Institute of Neurology Huashan Hospital Shanghai Medical College Fudan University Shanghai 200041 China Joint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto Zhejiang University Hangzhou 310009 China

Huntington's disease(HD)is an autosomal dominant degenerative disease that mainly encompasses movement,cognition,and behavioral *** apolipoprotein E(APOE)gene is thought to be associated with many neurodegenerative ***,we enrolled a cohort of 223 unrelated Han Chinese patients with HD and1241 unrelated healthy controls in Southeastern China and analyzed the correlation between APOE genotypes and HD *** results showed that the frequency of the E4 allele(7.1%)in HD patients was statistically less than that in controls(12.0%)(P =0.004).In addition,we divided patients into motor-onset and non-motor-onset groups,and analyzed the relationship with APOE *** results,however,were ***,the age at onset(AAO),defined as the age at the onset of motor symptoms,was compared in each APOE genotype subgroup and multivariate regression analysis was used to exclude the interference of CAG repeat length on AAO,but no association was found between APOE genotypes and ***,we analyzed adult-onset HD to exclude the interference caused by juvenile HD(n = 13),and the results were ***,our study suggests that APOE may not be a genetic modifier for HD,especially for adult-onset HD among Chinese of Han *** the best of our knowledge,this is the first study of the correlation between APOE genotypes and HD phenotypes in a Han Chinese population.

关键词： Huntington's disease Phenotype Apolipoprotein E Han Chinese population