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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 ***,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 ***,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 ***,DOK6 acts as an adaptor protein for selectivitymediated neurotrophic signal transduction and retrograde transport for TrkC and Ret but not for TrkA and ***6 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 *** 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

Single-neuron projectome-guided analysis reveals the neural circuit mechanism underlying endogenous opioid antinociception

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National Science Review 2024年第7期11卷 106-125页

作者： Yan-Nong Dou Yuan Liu Wen-Qun Ding Qing Li Hua Zhou Ling Li Meng-Ting Zhao Zheng-Yi-Qi Li Jing Yuan Xiao-Fei Wang Wang-Yuan Zou Anan Li Yan-Gang Sun institute of neuroscience Key Laboratory of Brain Cognition and Brain-Inspired Intelligence Technology CAS Center for Excellence in Brain Science&Intelligence Technology Chinese Academy of Sciences Department of Biology School of Life Science and TechnologyShanghaiTech University Lingang Laboratory University of Chinese Academy of Sciences Britton Chance Center for Biomedical Photonics Wuhan National Laboratory for OptoelectronicsMoE Key Laboratory for Biomedical Photonics Huazhong University of Science and Technology Department of Anesthesiology Xiangya HospitalCentral South University HUST-Suzhou institute for Brainsmatics JITRI

Endogenous opioid antinociception is a self-regulatory mechanism that reduces chronic pain, but its underlying circuit mechanism remains largely unknown. Here, we showed that endogenous opioid antinociception required the activation of mu-opioid receptors（MORs） in GABAergic neurons of the central amygdala nucleus（CEA） in a persistent-hyperalgesia mouse model. Pharmacogenetic suppression of these CEAMORneurons, which mimics the effect of MOR activation, alleviated the persistent ***, single-neuron projection analysis revealed multiple projectome-based subtypes of CEAMORneurons, each innervating distinct target brain regions. We found that the suppression of axon branches projecting to the parabrachial nucleus（PB） of one subtype of CEAMORneurons alleviated persistent hyperalgesia, indicating a subtype-and axonal-branch-specific mechanism of action. Further electrophysiological analysis revealed that suppression of a distinct CEA-PB disinhibitory circuit controlled endogenous opioid antinociception. Thus, this study identified the central neural circuit that underlies endogenous opioid antinociception, providing new insight into the endogenous pain modulatory mechanisms.

关键词： endogenous opioid antinociception mu-opioid receptors central amygdala nucleus parabrachial nucleus single-neuron projectome

Vascular endothelial growth factor:a double-edged sword in the development of white matter lesions

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Neural Regeneration Research 2025年第1期20卷 191-192页

作者： Narek Manukjan Daniel Fulton Zubair Ahmed WMatthijs Blankesteijn Sébastien Foulquier Department of Pharmacology and Toxicology Maastricht UniversityMaastrichtThe Netherlands CARIM-School for Cardiovascular Diseases Maastricht UniversityMaastrichtThe Netherlands neuroscience and Ophthalmology Institute of Inflammation and AgeingUniversity of BirminghamEdgbastonBirminghamUK Centre for Trauma Sciences Research University of BirminghamEdgbastonBirminghamUK MHeNs-School for Mental Health and neuroscience Maastricht UniversityMaastrichtThe Netherlands Department of Neurology Maastricht University Medical CenterMaastrichtThe Netherlands

As the population ages,the burden of age-related diseases becomes ***,over 55 million people suffer from dementia worldwide,with Alzheimer’s disease being the most common ***,it is becoming clearer that underlying vascular pathology such as cerebral small vessel disease(cSVD)may be a more detrimental cause for dementia(Cuadrado-Godia et al.,2018).It is estimated that 10%-30%of the elderly population and 35%-90%of all dementia patients exhibit signs of *** term cSVD refers to pathology affecting the small vessels of the brain,which can lead to lacunar cerebral infarcts,enlarged perivascular spaces,and cortical hemorrhages(Cuadrado-Godia et al.,2018).CSVD is often associated with cognitive decline,gait problems,and dementia(Cuadrado-Godia et al.,2018).

关键词： pathology becoming white

Changes in structural plasticity of hippocampal neurons in an animal model of multiple sclerosis

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Zoological Research 2024年第2期45卷 398-414页

作者： Poornima D.E.Weerasinghe-Mudiyanselage Sohi Kang Joong-Sun Kim Sung-Ho Kim Hongbing Wang Taekyun Shin Changjong Moon Department of Veterinary Anatomy and Animal Behavior College of Veterinary Medicine and BK21 FOUR ProgramChonnam National UniversityGwangju 61186Republic of Korea Department of Anatomy and Convergence Medical Science Institute of Health SciencesCollege of MedicineGyeongsang National UniversityJinju 52727Republic of Korea Department of Physiology and neuroscience Program Michigan State UniversityEast LansingMI 48824USA Department of Veterinary Anatomy College of Veterinary Medicine and Veterinary Medical Research InstituteJeju National UniversityJeju 63243Republic of Korea

Structural plasticity is critical for the functional diversity of neurons in the *** autoimmune encephalomyelitis(EAE)is the most commonly used model for multiple sclerosis(MS),successfully mimicking its key pathological features(inflammation,demyelination,axonal loss,and gliosis)and clinical symptoms(motor and non-motordysfunctions).Recentstudieshave demonstrated the importance of synaptic plasticity in EAE *** the present study,we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase(11 days post-immunization,DPI)and chronic phase(28DPI).EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic *** complexity was largely affected in the cornu ammonis 1(CA1)and CA3 apical and dentate gyrus(DG)subregions of the hippocampus during the chronic phase,while this effect was only noted in the CA1 apical subregion in the early ***,dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE,but only reduced in the DG subregion during the chronic ***,mRNA levels of proinflammatory cytokines(Il1β,Tnfα,and Ifnγ)and glial cell markers(Gfap and Cd68)were significantly increased,whereas the expression of activity-regulated cytoskeletonassociated protein(ARC)was reduced during the chronic ***,exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC *** cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase(ERK)phosphorylation upon treatment with proinflammatory ***,these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus,possibly through the ERK-ARC pathway,indicating that this alteration may be associated with hi

关键词： Activity-regulated cytoskeleton-associated protein Anxiety-like behavior Experimental autoimmune encephalomyelitis Hippocampal dysfunction Neuroinflammation

Cytisine N-methylene-(5，7，4’-trihydroxy)-isoflavone induces neural stem cell proliferation and reverses cognitive deficits in early Alzheimer's disease models via canonical Wnt/β-catenin pathway

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Food Science and Human Wellness 2024年

作者： Yang-Yang Lu Xiao-Wan Li Zhi-Ping Qin Wen-Jing Sun Yong-Biao Li Shao-Bo Liu Lu Lu Rong-Fei Yang Na-Na Zhang Yi-Ting Liu Jun Zhang Qing-Shan Liu Key Laboratory of Ethnomedicine for Ministry of Education， Center on Translational neuroscience， Minzu University of China Center for Life Sciences， School of Life Science and Technology， Harbin institute of Technology Department of Ophthalmology， Shandong Provincial Hospital Affiliated to Shandong First Medical University

Alzheimer’s disease (AD) is a degenerative disease of the central nervous system. It results in cognitive dysfunction due to the loss of functional neurons and a deficit of new neurons， which can lead to death in severe cases. Repairing damaged neurons by promoting hippocampal neurogenesis has become therapeutic modality to combat neurodegenerative diseases. The novel isoflavone alkaloid LY01， found in the edible fruits of Sophora alopecuroides L.， has various neuroprotective effects. However， the molecular mechanism by which it promotes the proliferation of endogenous neural stem cells (NSCs) is not yet precisely known. The effects of LY01 were investigated in vivo and in vitro. In vivo experiments showed that LY01 could counteract the toxic damage of Aβ， enhance the learning ability and memory capacity of 5×FAD mice， and improve the morphology of neurons in the hippocampal region. In vitro experiments showed that LY01 was effective against antioxidant damage， improved the cell morphology of C17.2 mouse NSCs after hydrogen peroxide injury， and increased cell viability. Both in vitro and in vivo experiments promoted NSC proliferation by upregulating the mRNA and protein levels of the critical genes of the Wnt/β-catenin pathway， which increased levels of doublecortin to facilitate new neuronal generation. This indicates that the ability of LY01 to counteract Aβ toxicity and alleviate oxidative damage in early AD is associated with activation of the Wnt/β-catenin signaling pathway to promote NSC proliferation and thus repair damaged neurons.

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Astrocytes dynamically regulate the blood-brain barrier in the healthy brain

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Neural Regeneration Research 2024年第4期19卷 709-710页

作者： AgnėPociūtė Augustas Pivoriūnas Alexei Verkhratsky Department of Stem Cell Biology State Research Institute Centre for Innovative MedicineVilniusLithuania Faculty of Biology Medicine and HealthThe University of ManchesterManchesterUK Achucarro Centre for neuroscience IKERBASQUEBasque Foundation for ScienceBilbaoSpain Department of Forensic Analytical Toxicology School of Forensic MedicineChina Medical UniversityShenyangLiaoning ProvinceChina

The blood-brain barrier(BBB)(discovered and defined by Max Lewandowsky and Lina Stern,and not,as it is universally,and yet erroneously believed,by Paul Ehrlich(Verkhratsky and Pivoriunas,2023))that separates the nervous system from the circulation is evolutionarily conserved from arthropods to *** primeval BBB of the invertebrates and some early vertebrates was made solely by glial cells and secured(in invertebrates)by septate junctions.

关键词： Ehrlich barrier blood

Real-time monitoring of oxygenation in deep brain tissue using a wireless photoelectric probe

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Science China Materials 2024年第4期67卷 1361-1362页

作者： Hao Pang Qilin Hua Guozhen Shen School of Integrated Circuits and Electronics Beijing Institute of TechnologyBeijing 100084China institute of Flexible Electronics Beijing Institute of TechnologyBeijing 102488China

Oxygen(O2) supply to the brain is of utmost importance for human health, as cerebral hypoxia can result in irreversible brain damage. Neurodegenerative diseases, such as epilepsy, are closely associated with cerebral hypoxia [1,2]. Real-time monitoring of cerebral oxygenation holds significant value in neuroscience research and clinical diagnostics [3–10].

关键词： epilepsy cerebral diseases

A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair

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Neural Regeneration Research 2025年第1期20卷 291-304页

作者： Simeon C.Daeschler Katelyn J.W.So Konstantin Feinberg Marina Manoraj Jenny Cheung Jennifer Zhang Kaveh Mirmoeini JPaul Santerre Tessa Gordon Gregory HBorschel SickKids Research institute Neuroscience and Mental Health ProgramTorontoONCanada institute of Biomaterials and Biomedical Engineering University of TorontoTorontoONCanada Indiana University School of Medicine IndianapolisINUSA Division of Plastic and Reconstructive Surgery the Hospital for Sick ChildrenTorontoONCanada Translational Biology and Engineering Program Ted Rogers Centre for Heart ResearchInstitute of Biomedical EngineeringFaculty of DentistryUniversity of TorontoTorontoONCanada

Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong ***,there are no FDA-approved therapies available to promote nerve *** accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve *** authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug *** is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 *** and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible *** released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic *** its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

关键词： biodegradable local drug delivery nerve injury nerve regeneration nerve wrap tacrolimus

Glycolysis and glucose metabolism as a target for bioenergetic and neuronal protection in glaucoma

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Neural Regeneration Research 2024年第8期19卷 1637-1638页

作者： Pete A.Williams Robert J.Casson Department of Clinical neuroscience Division of Eye and VisionSt.Erik Eye HospitalKarolinska InstitutetStockholmSweden Ophthalmic Research Laboratories Discipline of Ophthalmology and Visual SciencesUniversity of AdelaideAdelaideAustralia

Vision is arguably our most valued sense,yet approximately 340 million people globally suffer blindness or moderate visual impairment,highlighting the need to further develop and advance treatments for ophthalmic *** refers to a group of ocular disorders united by a clinically characteristic optic neuropathy with associated retinal ganglion cell loss.

关键词： metabolism glaucoma globally