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Docking protein 6 (DOK6) selectively docks the neurotrophic signaling transduction to restrain peripheral neuropathy

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1147-1164页

作者： Yan Guo Pan Xiang Xiaojiao Sun Wei Liu Jiafeng Zhou Bin Yin Lin Hou Boqin Qiang Huiliang Li Pengcheng Shu Xiaozhong Peng Department of Molecular Biology and Biochemistry Institute of Basic Medical SciencesMedical Primate Research CenterNeuroscience CenterChinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijingChina State key laboratory of Common Mechanism Research for Major Diseases Beijing 100005China Wolfson Institute for Biomedical Research University College LondonGower StreetLondon WC1E 6BTUK Chinese Institute for Brain Research Beijing 102206China State key laboratory of Respiratory Health and Multimorbidity Beijing 100005China Institute of laboratory Animal Science Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100021China

The appropriate and specific response of nerve cells to various external cues is essential for the establishment and maintenance of neural circuits,and this process requires the proper recruitment of adaptor molecules to selectively activate downstream pathways.Here,we identified that DOK6,a member of the Dok(downstream of tyrosine kinases)family,is required for the maintenance of peripheral axons,and that loss of Dok6 can cause typical peripheral neuropathy symptoms in mice,manifested as impaired sensory,abnormal posture,paw deformities,blocked nerve conduction,and dysmyelination.Furthermore,Dok6 is highly expressed in peripheral neurons but not in Schwann cells,and genetic deletion of Dok6 in peripheral neurons led to typical peripheral myelin outfolding,axon destruction,and hindered retrograde axonal transport.Specifically,DOK6 acts as an adaptor protein for selectivitymediated neurotrophic signal transduction and retrograde transport for TrkC and Ret but not for TrkA and TrkB.DOK6 interacts with certain proteins in the trafficking machinery and controls their phosphorylation,including MAP1B,Tau and Dynein for axonal transport,and specifically activates the downstream ERK1/2 kinase pathway to maintain axonal survival and homeostasis.This finding provides new clues to potential insights into the pathogenesis and treatment of hereditary peripheral neuropathies and other degenerative diseases.

关键词： impaired restrain peripheral

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Bioactive material promotes longdistance regeneration of optic nerve to restore visual functions

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Neural Regeneration Research 2024年第1期19卷 160-160页

作者： Kai Liu Division of Life Science State Key Laboratory of Molecular NeuroscienceThe Hong Kong University of Science and TechnologyHong Kong Special Administrative RegionChina

Visual system is vital to human beings.Unfortunately,the optic nerve lacks the ability to regenerate after injury.Therefo re,long-distance regeneration of the optic nerve is a major unsolved medical problem in the world(Laha et al.,2017).Recently,Li and So groups' study showed that the bioactive material(ciliary neurotrophic factor[CNTF]-chitosan) could promote long-distance regeneration of the completely transected optic nerve in adult rats and partially restored the visual functions(Liu et al.,2023).This study sheds light on the clinical potential for repairing the severely injured optic nerve.

关键词： visual Visual functions

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Temporal Unfolding of Racial Ingroup Bias in Neural Responses to Perceived Dynamic Pain in Others

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neuroscience Bulletin 2024年第2期40卷 157-170页

作者： Chenyu Pang Yuqing Zhou Shihui Han School of Psychological and Cognitive Sciences PKU-IDG/McGovern Institute for Brain ResearchBeijing Key Laboratory of Behavior and Mental HealthPeking UniversityBeijing 100081China CAS key laboratory of Behavioral Science Institute of PsychologyChinese Academy of SciencesBeijing 100101China Department of Psychology University of Chinese Academy of SciencesBeijing 100049China

In this study,we investigated how empathic neural responses unfold over time in different empathy networks when viewing same-race and other-race individuals in dynamic painful conditions.We recorded magnetoencephalography signals from Chinese adults when viewing video clips showing a dynamic painful(or non-painful)stimulation to Asian and White models’faces to trigger painful(or neutral)expressions.We found that perceived dynamic pain in Asian models modulated neural activities in the visual cortex at 100 ms–200 ms,in the orbitofrontal and subgenual anterior cingulate cortices at 150 ms–200 ms,in the anterior cingulate cortex around 250 ms–350 ms,and in the temporoparietal junction and middle temporal gyrus around 600 ms after video onset.Perceived dynamic pain in White models modulated activities in the visual,anterior cingulate,and primary sensory cortices after 500 ms.Our findings unraveled earlier dynamic activities in multiple neural circuits in response to same-race(vs other-race)individuals in dynamic painful situations.

关键词： Empathy Race Magnetoencephalography Dynamic pain Cingulate cortex

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Genetically modified non-human primate models for research on neurodegenerative diseases

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Zoological Research 2024年第2期45卷 263-274页

作者： Ming-Tian Pan Han Zhang Xiao-Jiang Li Xiang-Yu Guo Guangdong key laboratory of Non-human Primate Research Guangdong-Hongkong-Macao Institute of CNS RegenerationJinan UniversityGuangzhouGuangdong 510632China

Neurodegenerative diseases(NDs)are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease(AD),Parkinson's disease(PD),Huntington's disease(HD),and amyotrophic lateral sclerosis(ALS).Currently,there are no therapies available that can delay,stop,or reverse the pathological progression of NDs in clinical settings.As the population ages,NDs are imposing a huge burden on public health systems and affected families.Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments.While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms,the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap.Old World nonhuman primates(NHPs),such as rhesus,cynomolgus,and vervet monkeys,are phylogenetically,physiologically,biochemically,and behaviorally most relevant to humans.This is particularly evident in the similarity of the structure and function of their central nervous systems,rendering such species uniquely valuable for neuroscience research.Recently,the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms.This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained,as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.

关键词： Neurodegeneration Non-human primate Macaque monkey Animal model Gene modification

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Improvement in Tol2 transposon for efficient large-cargo capacity transgene applications in cultured cells and zebrafish(Danio rerio)

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Zoological Research 2024年第3期45卷 567-574页

作者： Peng-Cheng Wang Hao Deng Rang Xu Jiu-Lin Du Rongkun Tao Department of Pediatric Cardiology Xinhua HospitalShanghai Jiao Tong University School of MedicineShanghai 200092China Institute of neuroscience State Key Laboratory of NeuroscienceCenter for Excellence in Brain Science and Intelligence TechnologyChinese Academy of SciencesShanghai 200031China Medical School Kunming University of Science and TechnologyKunmingYunnan 650500China Scientific Research Center Xinhua HospitalShanghai Jiao Tong University School of MedicineShanghai 200092China University of Chinese Academy of Sciences Beijing 100049China School of Life Science and Technology ShanghaiTech UniversityShanghai 200031China

Most viruses and transposons serve as effective carriers for the introduction of foreign DNA up to 11 kb into vertebrate genomes.However,their activity markedly diminishes with payloads exceeding 11 kb.Expanding the payload capacity of transposons could facilitate more sophisticated cargo designs,improving the regulation of expression and minimizing mutagenic risks associated with molecular therapeutics,metabolic engineering,and transgenic animal production.In this study,we improved the Tol2 transposon by increasing protein expression levels using a translational enhancer(QBI SP163,ST)and enhanced the nuclear targeting ability using the nuclear localization protein H2B(SHT).The modified Tol2 and ST transposon efficiently integrated large DNA cargos into human cell cultures(H1299),comparable to the well-established super PiggyBac system.Furthermore,mRNA from ST and SHT showed a significant increase in transgene delivery efficiency of large DNA payloads(8 kb,14 kb,and 24 kb)into zebrafish(Danio rerio).This study presents a modified Tol2 transposon as an enhanced nonviral vector for the delivery of large DNA payloads in transgenic applications.

关键词： Zebrafish Tol2 transposase Transgene Large payload Synthetic biology

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High-throughput discovery of highly selective reversible hMAO-B inhibitors based on at-line nanofractionation

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1772-1786页

作者： Yu Fan Jincai Wang Jingyi Jian Yalei Wen Jiahao Li Hao Tian Jacques Crommen Wei Bi Tingting Zhang Zhengjin Jiang Institute of Pharmaceutical Analysis/Guangdong Province key laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/International Cooperative laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education(MOE)of China/College of Pharmacy Jinan UniversityGuangzhou 510632China KU Leuven-University of Leuven Pharmaceutical AnalysisDepartment of Pharmaceutical and Pharmacological SciencesLeuven 3000Belgium laboratory of Analytical Pharmaceutical Chemistry Department of Pharmaceutical SciencesCIRMUniversity of LiegeLiege B-4000Belgium Department of Neurology the First Affiliated Hospital of Jinan University/Clinical Neuroscience Institutethe First Affiliated Hospital of Jinan UniversityGuangzhou 510630China

Human monoamine oxidase B(hMAO-B)has emerged as a pivotal therapeutic target for Parkinson's disease.Due to adverse effects and shortage of commercial drugs,there is a need for novel,highly selective,and reversible hMAO-B inhibitors with good blood-brain barrier permeability.In this study,a high-throughput at-line nanofractionation screening platform was established with extracts from Chuanxiong Rhizoma,which resulted in the discovery of 75 active compounds,including phenolic acids,volatile oils,and phthalides,two of which were highly selective novel natural phthalide hMAO-B inhibitors that were potent,selective,reversible and had good blood‒brain permeability.Molecular docking and molecular dynamics simulations elucidated the inhibition mechanism.Sedanolide(IC_(50)=103 nmol/L;SI=645)and neocnidilide(IC_(50)=131 nmol/L;SI=207)demonstrated their excellent potential as hMAO-B inhibitors.They offset the limitations of deactivating enzymes associated with irreversible hMAO-B inhibitors such as rasagiline.In SH-SY5Y cell assays,sedanolide(EC_(50)=0.962μmol/L)and neocnidilide(EC_(50)=1.161μmol/L)exhibited significant neuroprotective effects,comparable to the positive drugs rasagiline(EC_(50)=0.896μmol/L)and safinamide(EC_(50)=1.079μmol/L).These findings underscore the potential of sedanolide as a novel natural hMAO-B inhibitor that warrants further development as a promising drug candidate.

关键词： Human monoamine oxidase B inhibitors High-throughput screening At-linenanofractionation Parkinson's disease Cellular neuroprotection Traditional Chinese medicines(TCMs)

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A Non-canonical Excitatory PV RGC–PV SC Visual Pathway for Mediating the Looming-evoked Innate Defensive Response

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neuroscience Bulletin 2024年第3期40卷 310-324页

作者： Man Yuan Sen Jin Gao Tan Siyuan Song Yizong Liu Huadong Wang Yin Shen Eye Center Renmin Hospital of Wuhan UniversityWuhan UniversityWuhan430060China The Brain Cognition and Brain Disease Institute Shenzhen Key Laboratory of Viral Vectors for BiomedicineShenzhen Institute of Advanced TechnologyChinese Academy of Sciences(CAS)Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research InstitutionsNational Medical Products Administration Key Laboratory for Research and Evaluation of Viral Vector Technology in Cell and Gene Therapy Medicinal ProductsShenzhen Key Laboratory of Quality Control Technology for Virus-Based TherapeuticsGuangdong Provincial Medical Products AdministrationShenzhen518055China Jan and Dan Duncan Neurological Research Institute Baylor College of MedicineHouston77030USA State key laboratory of Magnetic Resonance and Atomic and Molecular Physics Key Laboratory of Magnetic Resonance in Biological SystemsWuhan Center for Magnetic ResonanceInnovation Academy for Precision Measurement Science and TechnologyCASWuhan430071China Frontier Science Center of Immunology and Metabolism Medical Research InstituteWuhan UniversityWuhan430071China

Parvalbumin-positive retinal ganglion cells(PV+RGCs)are an essential subset of RGCs found in various species.However,their role in transmitting visual information remains unclear.Here,we characterized PV+RGCs in the retina and explored the functions of the PV+RGC-mediated visual pathway.By applying multiple viral tracing strategies,we investigated the downstream of PV+RGCs across the whole brain.Interestingly,we found that the PV+RGCs provided direct monosynaptic input to PV+excitatory neurons in the superficial layers of the superior colliculus(SC).Ablation or suppression of SC-projecting PV+RGCs abolished or severely impaired the flight response to looming visual stimuli in mice without affecting visual acuity.Furthermore,using transcriptome expression profiling of individual cells and immunofluorescence colocalization for RGCs,we found that PV+RGCs are predominant glutamatergic neurons.Thus,our findings indicate the critical role of PV+RGCs in an innate defensive response and suggest a non-canonical subcortical visual pathway from excitatory PV+RGCs to PV+SC neurons that regulates looming visual stimuli.These results provide a potential target for intervening and treating diseases related to this circuit,such as schizophrenia and autism.

关键词： Parvalbumin-positive retinal ganglion cell Innate fear Superior colliculus Excitatory-excitatory neuronal connection Looming-evoked defensive response Subcortical pathway

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Neural Circuitry Involving Substance P in Male Sexual Behavior

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neuroscience Bulletin 2024年第4期40卷 544-546页

作者： Xinrong Wang Junqiang Zheng Han Xu Department of Neurobiology and Department of Neurology of the Second Affiliated Hospital and School of Brain Science and Brain Medicine Zhejiang University School of MedicineHangzhou310058China Nanhu Brain-Computer Interface Institute Hangzhou311100China Liangzhu laboratory MOE Frontier Science Center for Brain Science and Brain-machine IntegrationState Key Laboratory of Brain-Machine IntelligenceZhejiang UniversityHangzhou311121China NHC and CAMS key laboratory of Medical Neurobiology Zhejiang UniversityHangzhou310058China Lingang laboratory Shanghai200031China

Male sexual behavior is an innate social behavior crucial for reproduction[1].Previous studies have identified several brain regions crucial for the control of both sexual and aggressive behaviors in males.Yet,molecularly specified neural circuits that specifically control male sexual behavior remain elusive.Consistent with the inherently rewarding nature of sexual behavior,previous research has implicated the role of the dopamine system in regulating sexual desire[2].However,the interaction between reward and copulation at the circuit level remains largely unexplored.Besides,it is unclear if the associated neural pathways are specific in modulating sexual reward.

关键词： behavior neural specified

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Multisensory Conflict Impairs Cortico-Muscular Network Connectivity and Postural Stability: Insights from Partial Directed Coherence Analysis

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neuroscience Bulletin 2024年第1期40卷 79-89页

作者： Guozheng Wang Yi Yang Kangli Dong Anke Hua Jian Wang Jun Liu key laboratory for Biomedical Engineering of Ministry of Education College of Biomedical Engineering&Instrument ScienceZhejiang UniversityHangzhou 310058China Taizhou key laboratory of Medical Devices and Advanced Materials Research Institute of Zhejiang University-TaizhouTaizhou 318000China Department of Sports Science College of EducationZhejiang UniversityHangzhou 310058China Center for Psychological Science Zhejiang UniversityHangzhou 310058China

Sensory conflict impacts postural control,yet its effect on cortico-muscular interaction remains underexplored.We aimed to investigate sensory conflict's influence on the cortico-muscular network and postural stability.We used a rotating platform and virtual reality to present subjects with congruent and incongruent sensory input,recorded EEG(electroencephalogram)and EMG(electromyogram)data,and constructed a directed connectivity network.The results suggest that,compared to sensory congruence,during sensory conflict:(1)connectivity among the sensorimotor,visual,and posterior parietal cortex generally decreases,(2)cortical control over the muscles is weakened,(3)feedback from muscles to the cortex is strengthened,and(4)the range of body sway increases and its complexity decreases.These results underline the intricate effects of sensory conflict on cortico-muscular networks.During the sensory conflict,the brain adaptively decreases the integration of conflicting information.Without this integrated information,cortical control over muscles may be lessened,whereas the muscle feedback may be enhanced in compensation.

关键词： Cortico-muscular interaction Postural control Virtual reality Electroencephalogram Electromyography Sensory integration

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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 protein.Atypical 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 disorders.The glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial fluid.Impairment 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 damage.Therefore,impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration.Previous 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 remain.This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related disorders.The 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 gliosis.This 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

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