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Nanopolyphenol rejuvenates microglial surveillance of multiple misfolded proteins through metabolic reprogramming

Acta Pharmaceutica Sinica B 2023年第2期13卷 834-851页

作者： Dayuan Wang Xiao Gu Xinyi Ma Jun Chen Qizhi Zhang Zhihua Yu Juan Li Meng Hu Xiaofang Tan Yuyun Tang Jianrong Xu Minjun Xu Qingxiang Song Huahua Song Gan Jiang Zaiming Tang Xiaoling Gao Hongzhuan Chen Department of Pharmacology and Chemical Biology State Key Laboratory of Oncogenes and Related GenesShanghai Universities Collaborative Innovation Center for Translational MedicineShanghai Jiao Tong University School of MedicineShanghai 200025China Key Laboratory of Smart Drug Delivery Ministry of EducationSchool of PharmacyFudan UniversityShanghai 201203China Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education Shanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203China

Microglial surveillance plays an essential role in clearing misfolded proteins such as amyloid-beta,tau,andα-synuclein aggregates in neurodegenerative diseases.However,due to the complex structure and ambiguous pathogenic species of the misfolded proteins,a universal approach to remove the misfolded proteins remains unavailable.Here,we found that a polyphenol,α-mangostin,reprogrammed metabolism in the disease-associated microglia through shifting glycolysis to oxidative phosphorylation,which holistically rejuvenated microglial surveillance capacity to enhance microglial phagocytosis and autophagy-mediated degradation of multiple misfolded proteins.Nanoformulation ofα-mangostin efficiently deliveredα-mangostin to microglia,relieved the reactive status and rejuvenated the misfolded-proteins clearance capacity of microglia,which thus impressively relieved the neuropathological changes in both Alzheimer’s disease and Parkinson’s disease model mice.These findings provide direct evidences for the concept of rejuvenating microglial surveillance of multiple misfolded proteins through metabolic reprogramming,and demonstrate nanoformulatedα-mangostin as a potential and universal therapy against neurodegenerative diseases.

关键词： Microglia Metabolism Misfolded proteins Phagocytosis Degradation Polyphenol Nanoparticles neurodegenerative diseases

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Protein amyloid aggregate:Structure and function

聚集体(英文)

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聚集体(英文) 2023年第4期4卷 55-70页

作者： Qianhui Xu Yeyang Ma Yunpeng Sun Dan Li Xin Zhang Cong Liu Interdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghaiChina Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersMinistry of EducationShanghai Jiao Tong UniversityShanghaiChina Zhangjiang Institute for Advanced Study Shanghai Jiao Tong UniversityShanghaiChina Department of Chemistry and Westlake Laboratory of Life Sciences and Biomedicine Westlake UniversityHangzhouChina State Key Laboratory of Bio-Organic and Natural Products Chemistry Shanghai Institute of Organic ChemistryUniversity of Chinese Academy of SciencesShanghaiChina

Protein amyloid aggregation has been widely observed to occur and plays impor-tant roles in both physiological processes and pathological diseases.Remarkably,amyloid aggregates assembled by native proteins gain a variety of different biolog-ical activities,which cannot be adopted by the unassembled protein alone.Thus,it is important to investigate the molecular basis of self-assembly of protein amyloid aggregates and how the aggregated protein structure determines its function.In the review,wefirstly introduce our structural knowledge on how different amyloid pro-teins undergo conformational transition and assemble into amyloid aggregate,with the main focus on amyloidfibril,which is the major species of amyloid aggregate.Then,we elaborate how different structures of amyloidfibrils enable them to fulfill highly diverse functions in either physiological or pathological condition.Further-more,we discuss the structural polymorph which is a very unique feature of amyloidfibril,and its implication in understanding the structure-function relationship of amy-loidfibrils.Finally,we point out the importance of applying and integrating new approaches for deepening the structure-function study of amyloidfibrils and high-light the potential of designing amyloidfibril-based functional bio-nanomaterials for application.

关键词： amyloidfibril neurodegenerative diseases prion-like propagation protein phase separation protein aggregate

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Investigating Müller glia reprogramming in mice: a retrospective of the last decade, and a look to the future

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Neural Regeneration Research 2025年第4期20卷 946-959页

作者： Zhiyuan Yin Jiahui Kang Xuan Cheng Hui Gao Shujia Huo Haiwei Xu Key Lab of Visual Damage and Regeneration&Restoration of Chongqing Southwest Eye HospitalSouthwest HospitalThird Military Medical University(Army Medical University)ChongqingChina

Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased states.In lower vertebrates like zebrafish,these cells assume responsibility for spontaneous retinal regeneration,wherein endogenous Müller glia undergo proliferation,transform into Müller glia-derived progenitor cells,and subsequently regenerate the entire retina with restored functionality.Conversely,Müller glia in the mouse and human retina exhibit limited neural reprogramming.Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders.Müller glia reprogramming in mice has been accomplished with remarkable success,through various technologies.Advancements in molecular,genetic,epigenetic,morphological,and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice.Nevertheless,there remain issues that hinder improving reprogramming efficiency and maturity.Thus,understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency,and for developing novel Müller glia reprogramming strategies.This review describes recent progress in relatively successful Müller glia reprogramming strategies.It also provides a basis for developing new Müller glia reprogramming strategies in mice,including epigenetic remodeling,metabolic modulation,immune regulation,chemical small-molecules regulation,extracellular matrix remodeling,and cell-cell fusion,to achieve Müller glia reprogramming in mice.

关键词： cell fusion chemical small-molecules epigenetic extracellular matrix immune metabolic mice Müller glia neurodegenerative diseases reprogramming retina regeneration

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Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration Research 2025年第3期20卷 725-739页

作者： Benjamin R.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler Department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Center for Molecular Innovation and Drug Discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam Center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg School of Medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

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Nanomaterials-mediated lysosomal regulation:a robust protein-clearance approach for the treatment of Alzheimer’s disease

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Neural Regeneration Research 2025年第2期20卷 424-439页

作者： Mengqi Hao Jianjian Chu Tinglin Zhang Tong Yin Yuankai Gu Wendanqi Liang Wenbo Ji Jianhua Zhuang Yan Liu Jie Gao You Yin Department of Neurology Second Affiliated Hospital of Naval Medical University(Shanghai Changzheng Hospital)ShanghaiChina School of Health Science and Engineering University of Shanghai for Science and TechnologyShanghaiChina Changhai Clinical Research Unit Shanghai Changhai HospitalNaval Medical UniversityShanghaiChina Department of Clinical Pharmacy Xinhua HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Neurology Shanghai East HospitalSchool of MedicineTongji UniversityShanghaiChina

Alzheimer’s disease is a debilitating,progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins,including amyloid plaques and intracellular tau tangles,primarily within the brain.Lysosomes,crucial intracellular organelles responsible for protein degradation,play a key role in maintaining cellular homeostasis.Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases,including Alzheimer’s disease.Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer’s disease.Currently,the efficacy of drugs in treating Alzheimer’s disease is limited,with major challenges in drug delivery efficiency and targeting.Recently,nanomaterials have gained widespread use in Alzheimer’s disease drug research owing to their favorable physical and chemical properties.This review aims to provide a comprehensive overview of recent advances in using nanomaterials(polymeric nanomaterials,nanoemulsions,and carbon-based nanomaterials)to enhance lysosomal function in treating Alzheimer’s disease.This review also explores new concepts and potential therapeutic strategies for Alzheimer’s disease through the integration of nanomaterials and modulation of lysosomal function.In conclusion,this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer’s disease.The application of nanotechnology to the development of Alzheimer’s disease drugs brings new ideas and approaches for future treatment of this disease.

关键词： Alzheimer’s disease autophagy dysfunction lysosomal acidification lysosomal system nanomaterials neurodegenerative diseases

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Microglia lactylation in relation to central nervous system diseases

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Neural Regeneration Research 2025年第1期20卷 29-40页

作者： Hui Yang Nan Mo Le Tong Jianhong Dong Ziwei Fan Mengxian Jia Juanqing Yue Ying Wang School of Pharmacy Hangzhou Normal UniversityHangzhouZhejiang ProvinceChina Department of Clinical Laboratory The Fourth Clinical Medical College of Zhejiang University of Traditional Chinese Medicine(Hangzhou First People’s Hospital)HangzhouZhejiang ProvinceChina College of Medical Veterinary and Life SciencesUniversity of GlasgowGlasgowUK Department of Orthopedics(Spine Surgery) the First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina Department of Pathology Affiliated Hangzhou First People’s HospitalWestlake University School of MedicineHangzhouZhejiang ProvinceChina Department of Clinical Research Center Affiliated Hangzhou First People’s HospitalWestlake University School of MedicineHangzhouZhejiang ProvinceChina

The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous system homeostasis,injury response,and neurodegenerative diseases.Lactate has been considered a metabolic waste product,but recent studies are revealing ever more of the physiological functions of lactate.Lactylation is an important pathway in lactate function and is involved in glycolysis-related functions,macrophage polarization,neuromodulation,and angiogenesis and has also been implicated in the development of various diseases.This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation,histone versus non-histone lactylation,and therapeutic approaches targeting lactate.Finally,we summarize the current research on microglia lactylation in central nervous system diseases.A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.

关键词： brain central nervous system glycolysis immune response inflammation lactate metabolism lactate lactylation microglia neurodegenerative diseases

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Fibroblasts:New players in the central nervous system?

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Fundamental Research 2024年第2期4卷 262-266页

作者： Lihui Duan Xiang Yu State Key Laboratory of Molecular Development Biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Membrane Biology School of Life SciencesPeking UniversityBeijing 100871China Peking-Tsinghua Center for Life Sciences and Peking University McGovern Institute Peking UniversityBeijing 100871China Chinese Institute for Brain Research Beijing 102206China

Fibroblasts are typically described as cells that produce extracellular matrix,contribute to the formation of connective tissue,and maintain the structural framework of tissues.Fibroblasts are the first cell type to be transdifferentiated into inducible pluripotent stem cells(iPSCs),demonstrating their versatility and reprogrammability.Currently,there is relatively extensive characterization of the anatomical,molecular,and functional diversity of fibroblasts in different peripheral organs and tissues.With recent advances in single cell RNA sequencing,heterogeneity and diversity of fibroblasts in the central nervous system(CNS)have also begun to emerge.Based on their distinct anatomical locations in the meninges,perivascular space,and choroid plexus,as well as their molecular diversity,important roles for fibroblasts in the CNS have been proposed.Here,we draw inspirations from what is known about fibroblasts in peripheral tissues,in combination with their currently identified CNS locations and molecular characterizations,to propose potential functions of CNS fibroblasts in health and disease.Future studies,using a combination of technologies,will be needed to determine the bona fide in vivo functions of fibroblasts in the CNS.

关键词： Fibroblasts Central nervous system Infection Aging neurodegenerative diseases Injury

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Possible role of glial cell line-derived neurotrophic factor for predicting cognitive impairment in Parkinson’s disease:a case-control study

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Neural Regeneration Research 2021年第5期16卷 885-892页

作者： Ming-Yu Shi Cheng-Cheng Ma Fang-Fang Chen Xiao-Yu Zhou Xue Li Chuan-Xi Tang Lin Zhang Dian-Shuai Gao Department of Neurology the Affiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsu ProvinceChina Department of Neurology the First People’s Hospital of YanchengYanchengJiangsu ProvinceChina Department of Neurobiology and Anatomy Xuzhou Key Laboratory of NeurobiologyXuzhou Medical UniversityXuzhouJiangsu ProvinceChina Department of Neurology Suqian First People’s HospitalSuqianJiangsu ProvinceChina Department of Operating Room the Affiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsu ProvinceChina

Glial cell line-derived neurotrophic factor(GDNF)plays an important role in the protection of dopaminergic neurons,but there are few reports of the relationship between GDNF and its precursors(α-pro-GDNF andβ-pro-GDNF)and cognitive impairment in Parkinson’s disease.This study aimed to investigate the relationship between the serum levels of GDNF and its precursors and cognitive impairment in Parkinson’s disease,and to assess their potential as a diagnostic marker.Fifty-three primary outpatients and hospitalized patients with Parkinson’s disease(23 men and 30 women)with an average age of 66.58 years were enrolled from the Affiliated Hospital of Xuzhou Medical University of China in this case-control study.The patients were divided into the Parkinson’s disease with cognitive impairment group(n=27)and the Parkinson’s disease with normal cognitive function group(n=26)based on their Mini-Mental State Examination,Montreal Cognitive Assessment,and Clinical Dementia Rating scores.In addition,26 age-and sex-matched healthy subjects were included as the healthy control group.Results demonstrated that serum GDNF levels were significantly higher in the Parkinson’s disease with normal cognitive function group than in the other two groups.There were no significant differences in GDNF precursor levels among the three groups.Correlation analysis revealed that serum GDNF levels,GDNF/α-pro-GDNF ratios,and GDNF/β-pro-GDNF ratios were moderately or highly correlated with the Mini-Mental State Examination,Montreal Cognitive Assessment,and Clinical Dementia Rating scores.To explore the risk factors for cognitive impairment in patients with Parkinson’s disease,logistic regression analysis and stepwise linear regression analysis were performed.Both GDNF levels and Hoehn-Yahr stage were risk factors for cognitive impairment in Parkinson’s disease,and were the common influencing factors for cognitive scale scores.Neitherα-pro-GDNF norβ-pro-GDNF was risk factors for cognitive impairment in Parkinson’s disease.A receiver operating character

关键词： biomarkers cognition factors GDNF neurodegenerative diseases neurons Parkinson’s disease risk factors

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Saccharomyces cerevisiae in neuroscience:how unicellular organism helps to better understand prion protein?

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Neural Regeneration Research 2021年第3期16卷 489-495页

作者： Takao Ishikawa Department of Molecular Biology Institute of BiochemistryFaculty of BiologyUniversity of WarsawWarsawPoland

The baker's yeast Saccharomyces(S.)cerevisiae is a single-celled eukaryotic model organism widely used in research on life sciences.Being a unicellular organism,S.cerevisiae has some evident limitations in application to neuroscience.However,yeast prions are extensively studied and they are known to share some hallmarks with mammalian prion protein or other amyloidogenic proteins found in the pathogenesis of Alzheimer's,Parkinson's,or Huntington's diseases.Therefore,the yeast S.cerevisiae has been widely used for basic research on aggregation properties of proteins in cellulo and on their propagation.Recently,a yeast-based study revealed that some regions of mammalian prion protein and amyloidβ1–42 are capable of induction and propagation of yeast prions.It is one of the examples showing that evolutionarily distant organisms share common mechanisms underlying the structural conversion of prion proteins making yeast cells a useful system for studying mammalian prion protein.S.cerevisiae has also been used to design novel screening systems for anti-prion compounds from chemical libraries.Yeastbased assays are cheap in maintenance and safe for the researcher,making them a very good choice to perform preliminary screening before further characterization in systems engaging mammalian cells infected with prions.In this review,not only classical red/white colony assay but also yeast-based screening assays developed during last year are discussed.Computational analysis and research carried out using yeast prions force us to expect that prions are widely present in nature.Indeed,the last few years brought us several examples indicating that the mammalian prion protein is no more peculiar protein–it seems that a better understanding of prion proteins nature-wide may aid us with the treatment of prion diseases and other amyloid-related medical conditions.

关键词： amyloid artificial prion baker's yeast budding yeast drug screening fusion protein neurodegenerative diseases prion protein yeast-based assay

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Recent advances in lentiviral vectors for gene therapy

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Science China(Life Sciences) 2021年第11期64卷 1842-1857页

作者： Xiaoyu Wang Cuicui Ma Roberto Rodríguez Labrada Zhou Qin Ting Xu Zhiyao He Yuquan Wei Department of Pharmacy State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China Department Clinical Neurophysiology Centre for the Research and Rehabilitation of Hereditary AtaxiasHolguín 80100Cuba Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

Lentiviral vectors(LVs), derived from human immunodeficiency virus, are powerful tools for modifying the genes of eukaryotic cells such as hematopoietic stem cells and neural cells. With the extensive and in-depth studies on this gene therapy vehicle over the past two decades, LVs have been widely used in both research and clinical trials. For instance, third-generation and selfinactive LVs have been used to introduce a gene with therapeutic potential into the host genome and achieve targeted delivery into specific tissue. When LVs are employed in leukemia, the transduced T cells recognize and kill the tumor B cells;in β-thalassemia, the transduced CD34^(+) cells express normal β-globin;in adenosine deaminase-deficient severe combined immunodeficiency, the autologous CD34^(+) cells express adenosine deaminase and realize immune reconstitution. Overall, LVs can perform significant roles in the treatment of primary immunodeficiency diseases, hemoglobinopathies, B cell leukemia, and neurodegenerative diseases. In this review, we discuss the recent developments and therapeutic applications of LVs. The safe and efficient LVs show great promise as a tool for human gene therapy.

关键词： lentiviral vector gene therapy primary immunodeficiency diseases leukemia hemoglobinopathies neurodegenerative diseases

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