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The big data challenge-and how polypharmacology supports the translation from pre-clinical research into clinical use against neurodegenerative diseases and beyond

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Neural Regeneration Research 2024年第8期19卷 1647-1648页

作者： Sven Marcel Stefan Muhammad Rafehi Drug Development and Chemical Biology Lübeck Institute of Experimental Dermatology(LIED)University of Lübeck and University Medical Center Schleswig-HolsteinLübeckGermany Department of Pathology Section of NeuropathologyTranslational Neurodegeneration Research and Neuropathology LabUniversity of Oslo and Oslo University HospitalOsloNorway School of Medical Sciences Faculty of Medicine and HealthUniversity of SydneySydneyNSWAustralia Institute of Clinical Pharmacology University Medical Center GöttingenGöttingenGermany Department of Medical Education Augsburg University MedicineAugsburgGermany

Introductory comments:The identification and validation of disease-modifying proteins are fundamental aspects in drug ***,the m ultifactority of n eurodegen era tive diseases poses a real challenge for targeted ***,the behavior of individually(over-)expressed to rget proteins in vitro is likely to differ from their actual functional behavior when embedded in cascades and pathways in vivo.

关键词： translation beyond likely

Is tuberous sclerosis complex-associated autism a preventable andtreatabledisorder?

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World Journal of Pediatrics 2024年第1期20卷 40-53页

作者： Paolo Curatolo Mirte Scheper Leonardo Emberti Gialloreti Nicola Specchio Eleonora Aronica Child Neurology and Psychiatry unit Systems Medicine DepartmentTor Vergata UniversityRomeItaly Department of neuropathology Amsterdam NeuroscienceAmsterdam UMC Location University of AmsterdamAmsterdamTheNetherlands Department of Biomedicine and Prevention University of Rome Tor VergataVia Montpellier 100133 RomeItaly Clinical and Experimental Neurology Bambino Gesù Children's HospitalIRCCSFull Member of European ReferenceNetworkEpiCAREPiazza S.Onofrio400165 RomeItaly Stichting Epilepsie Instellingen Nederland(SEIN) HeemstedeAmsterdamThe Netherlands

Background Tuberous sclerosis complex(TSC)is a genetic disorder caused by inactivating mutations in the TSCl and TSC2 genes,causing overactivation of the mechanistic(previously referred to as mammalian)target of rapamycin(mTOR)signaling pathway in fetal *** mTOR pathway plays a crucial role in several brain processes leading to TSC-related epilepsy,intellectual disability,and autism spectrum disorder(ASD).Pre-natal or early post-natal diagnosis of TSC is now possible in a growing number of pre-symptomatic *** sources We searched PubMed for peer-reviewed publications published between January 2010 and April 2023 with the terms“tuberous sclerosis",“autism",or“autism spectrum disorder""animal models",“preclinical studies",“neurobiology",and“treatment".Results Prospective studies have highlighted that developmental trajectories in TSC infants who were later diagnosed with ASD already show motor,visual and social communication skills in the first year of life *** genetic,cellular,electroencephalography and magnetic resonance imaging biomarkers can identify pre-symptomatic TSC infants at high risk for having autism and *** Preventing epilepsy or improving therapy for seizures associated with prompt and tailored treatment strategies for autism in a sensitive developmental time window could have the potential to mitigate autistic symptoms in infants with TSC.

关键词： Animal model-Autism spectrum disorders Developmental and epileptic encephalopathy Mechanisms mTOR Risk Tuberos sclerosis complex

PML nuclear bodies:new players in familial amyotrophic lateral sclerosis-frontotemporal dementia?

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Neural Regeneration Research 2024年第9期19卷 1875-1876页

作者： Anand Goswami Serena Carra Institute of neuropathology RWTH Aachen University HospitalAachenGermany Department of Neurology Eleanor and Lou Gehrig ALS CenterColumbia UniversityNew YorkNYUSA Department of Biomedical Metabolic and Neural SciencesUniversity of Modena and Reggio EmiliaModenaItaly

Amyotrophi c lateral s c lerosis(ALS)and frontotemporal dementia(FTD)are two closely related disorders with overlapping clinical,genetic,and neuropathological features,forming a continuous disease spectrum(Ling et al.,2013).The major pathological hallmark of ALS and FTD are the depletion from the nucleus of the RNA-binding proteins TAR DNA‐binding protein 43(TDP-43)and FUsed in Sarcoma(FUS)and their abnormal accumulation in ubiquitin-positive cytoplasmic inclusions(Ling et al.,2013).

关键词： clinical familial

Substrate topography as a powerful tool to modify glial cell biology and interactions

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Neural Regeneration Research 2025年第5期20卷 1390-1391页

作者： Pascal Achenbach Haktan Altinova Gary A.Brook Institute of neuropathology RWTH Aachen University Hospital Department of Neurosurgery RWTH Aachen University Hospital Aachen Germany Berlin State Office for Health and Social Affairs(LAGeSo) BerlinGermany

Traumatic injuries to the central nervous system(CNS) result in disruption of the intricate network of axons which connect functionally related neurons that are widely distributed throughout the brain and spinal *** normal conditions,maintenance of this complex system is structurally and functionally supported by astrocytes (ACs)and other glial cells,the processes of which form a framework surrounding neuronal cell bodies,dendrites,axons,and synapses.

关键词： injuries topography system

Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape

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Signal Transduction and Targeted Therapy 2024年第1期9卷 326-337页

作者： You Zhai Yicong Du Guanzhang Li Mingchen Yu Huimin Hu Changqing Pan Di Wang Zhongfang Shi Xu Yan Xuesong Li Tao Jiang Wei Zhang Department of Molecular neuropathology Beijing Neurosurgical InstituteCapital Medical UniversityBeijingPR China Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijingPR China Department of Urology Peking University First HospitalInstitute of UrologyPeking UniversityNational Urological Cancer CenterBeijingPR China Department of Pathophysiology Beijing Neurosurgical InstituteCapital Medical UniversityBeijingPR China China National Clinical Research Center for Neurological Diseases BeijingPR China Center of Brain Tumor Beijing Institute for Brain DisordersBeijingPR China Research unit of Accurate Diagnosis Treatmentand Translational Medicine of Brain TumorsChinese Academy of Medical SciencesBeijingPR China Chinese Glioma Genome Atlas Network(CGGA)and Asian Glioma Genome Atlas Network(AGGA) BeijingPR China

Chimeric antigen receptor(CAR)T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid *** instances of rapid tumor remissions have been observed in animal models and clinical trials,tumor relapses occur with multiple therapeutic resistance ***,while the mechanisms underlying the long-term therapeutic resistance are well-known,short-term adaptation remains less ***,more views shed light on short-term adaptation and hold that it provides an opportunity window for long-term *** this study,we explore a previously unreported mechanism in which tumor cells employ trogocytosis to acquire CAR molecules from CAR-T cells,a reversal of previously documented *** mechanism results in the depletion of CAR molecules and subsequent CAR-T cell dysfunction,also leading to short-term antigen loss and antigen *** type of intercellular communication is independent of CAR downstream signaling,CAR-T cell condition,target antigen,and tumor cell ***,it is mainly dependent on antigen density and CAR sensitivity,and is associated with tumor cell cholesterol *** mitigation of this trogocytosis-induced CAR molecule transfer can be achieved by adaptively administering CAR-T cells with antigen density-individualized CAR ***,our study reveals a dynamic process of CAR molecule transfer and refining the framework of clinical CAR-T therapy for solid tumors.

关键词： Together instance depletion

New insights into the therapeutic approaches for the treatment of tauopathies

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Neural Regeneration Research 2024年第5期19卷 1020-1026页

作者： Himanshi Singh Asmita Das Mohammad Moshahid Khan Tayebeh Pourmotabbed Department of Microbiology Immunology and BiochemistryUniversity of Tennessee Health Science CenterMemphisTNUSA Department of Biotechnology Delhi Technological UniversityShahbad DaulatpurDelhiIndia Department of Neurology College of MedicineUniversity of Tennessee Health Science CenterMemphisTNUSA Neuroscience Institute University of Tennessee Health Science CenterMemphisTNUSA Center for Muscle Metabolism and NeuropathologyDivision of Regenerative and Rehabilitation Sciences and Department of Physical TherapyCollege of Health ProfessionsUniversity of Tennessee Health Science CenterMemphisTNUSA

Tauopathies are a group of neurological disorders,including Alzheimer’s disease and frontotemporal dementia,which involve progressive neurodegeneration,cognitive deficits,and aberrant tau protein *** development of tauopathies cannot currently be stopped or slowed down by treatment *** the significant contribution of tau burden in primary tauopathies and the strong association between pathogenic tau accumulation and cognitive deficits,there has been a lot of interest in creating therapies that can alleviate tau pathology and render neuroprotective ***,small molecules,immunotherapies,and gene therapy have been used to reduce the pathological tau burden and prevent neurodegeneration in animal models of ***,the major pitfall of the current therapeutic approach is the difficulty of drugs and gene-targeting modalities to cross the blood-brain barrier and their unintended side *** this review,the current therapeutic strategies used for tauopathies including the use of oligonucleotide-based gene therapy approaches that have shown a promising result for the treatment of tauopathies and Alzheimer’s disease in preclinical animal models,have been discussed.

关键词： dementia gene therapies immunotherapy neurodegeneration oligonucleotides tau tauopathies therapies

Repressing iron overload ameliorates central poststroke pain via the Hdac2-Kv1.2 axis in a rat model of hemorrhagic stroke

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Neural Regeneration Research 2024年第12期19卷 2708-2722页

作者： He Fang Mengjie Li Jingchen Yang Shunping Ma Li Zhang Hongqi Yang Qiongyan Tang Jing Cao Weimin Yang Department of Neurology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina Department of Molecular neuropathology Beijing Neurosurgical InstituteCapital Medical UniversityBeijingChina Department of Nutrition The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina Department of Neurology Henan Provincial People’s HospitalZhengzhouHenan ProvinceChina Department of Human Anatomy School of Basic Medical SciencesZhengzhou UniversityZhengzhouHenan ProvinceChina Neuroscience Research Institute Zhengzhou University Academy of Medical SciencesZhengzhouHenan ProvinceChina

Thalamic hemorrhage can lead to the development of central post-stroke *** in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrhagic ***,the regulato ry mechanism of histone deacetylases in central post-stroke pain remains unclea ***,we show that iron overload leads to an increase in histone deacetylase 2expression in damaged ventral posterolateral nucleus *** this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium(Kv)channel subunit gene in a rat model of central post-stroke pain,thereby increasing Kcna2expression and relieving central ***,in the absence of nerve injury,increasing histone deacetylase 2 expression decreased Kcna2expression,decreased Kv current,increased the excitability of neurons in the ventral posterolateral nucleus area,and led to neuropathic pain ***,treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage,reversed histone deacetylase 2 upregulation and Kv1.2 downregulation,and alleviated mechanical hypersensitivity in central post-stroke pain *** results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation,mediated by iron overload,are important factors in central post-stroke pain pathogenesis and co uld se rve as new to rgets for central poststroke pain treatment.

关键词： central post-stroke pain hemorrhagic stroke histone deacetylase iron overload voltage-gated potassium ion channel 1.2

The clinical,radiological,and surgical characteristics of anterior perforated substance glioma:a retrospective study

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Chinese Neurosurgical Journal 2024年第1期10卷 28-34页

作者： Zhiliang Wang Lianwang Li Zheng Wang Xuzhu Chen Zhong Zhang Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityNo.119 South 4th Ring West RoadBeijing 100070People’s Republic of China Department of Molecular neuropathology Beijing Neurosurgical InstituteCapital Medical UniversityBeijingChina Department of Radiology Beijing Neurosurgical InstituteCapital Medical UniversityBeijingChina Department of Radiology Beijing Tiantan HospitalCapital Medical UniversityNo.119 South 4th Ring West RoadBeijing 100070People’s Republic of China

Background To explore the clinical,radiological,and surgical characteristics of anterior perforated substance(APS)*** Twenty patients with APS glioma who were treated with surgery between March 2019 and January 2022 from Tiantan hospital were retrospectively *** clinical,histological and radiological data were *** Twenty patients,including 7 males(55%)and 13 females(45%),with a mean age at diagnosis of 37.9 years(range,28-53 years)underwent operative intervention for *** and dizziness were the most common preoperative symptoms in the majority patients(14,70%).Based on radiological features of MRI,the APS was classified into two subtypes,type A and type *** patients(40%)in type A indicated a clear tumor margin,while 13 patients(60%)in type B showed an ill-defined *** surgical approach including frontal,temporal,and coronal frontal incisions for type A and type B tumors,*** patients in type A received total resection,while one patient in type B were total ***,12 cases(60%,12/20)were diagnosed as astrocytoma and 8 cases(20%,8/20)were ***,17 cases(85%,17/20)had MGMT promotor *** In this study,we performed the first systematic research of patients with APS *** of patients with APS presented headaches and dizziness *** APS glioma was further divided into two major radiological subtypes with relevant different surgical *** APS glioma in type A were more likely to receive total resection.

关键词： Anterior perforated substance Glioma Magnetic resonance imaging Operation

From cradle to grave: neurogenesis, neuroregeneration and neurodegeneration in Alzheimer’s and Parkinson’s diseases

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Neural Regeneration Research 2022年第12期17卷 2606-2614页

作者： Debia Wakhloo Jane Oberhauser Angela Madira Sameehan Mahajani Deparment of neuropathology Stanford UniversitySchool of MedicineStanfordCAUSA

Two of the most common neurodegenerative disorders-Alzheimer’s and Parkinson’s diseases-are characterized by synaptic dysfunction and degeneration that culminate in neuronal loss due to abnormal protein *** intracellular aggregation of hyper-phosphorylated tau and the extracellular aggregation of amyloid beta plaques form the basis of Alzheimer’s disease *** major hallmark of Parkinson’s disease is the loss of dopaminergic neurons in the substantia nigra pars compacta,following the formation of Lewy bodies,which consists primarily of alpha-synuclein ***,the discrete mechanisms that contribute to neurodegeneration in these disorders are still poorly *** neuronal loss and impaired adult neurogenesis have been reported in animal models of these *** these findings remain subject to frequent debate due to a lack of conclusive evidence in post mortem brain tissue from human *** some publications provide significant findings related to axonal regeneration in Alzheimer’s and Parkinson’s diseases,they also highlight the limitations and obstacles to the development of neuroregenerative *** this review,we summarize in vitro and in vivo findings related to neurogenesis,neuroregeneration and neurodegeneration in the context of Alzheimer’s and Parkinson’s diseases.

关键词： alpha-synuclein amyloid beta plaques autophagy dopaminergic neurons human iPSCs mitochondrial dysfunction scRNA sequencing synaptic dysfunction Tau Wallerian degeneration