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Translating Pathological Brain Activity Primers in Parkinson’s Disease Research

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Research 2024年第1期2023卷 735-752页

作者： Daniela Mirzac Svenja L.Kreis Heiko J.Luhmann Gabriel Gonzalez-Escamilla Sergiu Groppa Movement disorders and Neurostimulation Department of NeurologyFocus Program Translational NeuroscienceRhine Main Neuroscience NetworkUniversity Medical Center of the Johannes Gutenberg University Mainz55131 MainzGermany Institute of Physiology University Medical Center of the Johannes Gutenberg University Mainz55131 MainzGermany

Translational experimental approaches that help us better trace Parkinson’s disease(PD)pathophysiological mechanisms leading to new therapeutic targets are urgently *** this article,we review recent experimental and clinical studies addressing abnormal neuronal activity and pathological network oscillations,as well as their underlying mechanisms and *** aim is to enhance our knowledge about the progression of Parkinson's disease pathology and the timing of its symptom’s ***,we present mechanistic insights relevant for the generation of aberrant oscillatory activity within the cortico-basal ganglia *** summarize recent achievements extrapolated from available PD animal models,discuss their advantages and limitations,debate on their differential applicability,and suggest approaches for transferring knowledge on disease pathology into future research and clinical applications.

关键词： clinical knowledge insight

Perspectives for delivery of therapeutics by extravasation of biodegradable microspheres in the brain

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Neural Regeneration Research 2024年第5期19卷 969-970页

作者： Anne-Eva van der Wijk Ed VanBavel Amsterdam UMC location University of Amsterdam Department of Biomedical Engineering and PhysicsAmsterdamThe Netherlands Amsterdam neuroscience Neurovascular Disorders ProgramAmsterdamThe Netherlands Amsterdam Cardiovascular Sciences Microcirculation ProgramAmsterdamThe Netherlands

Development of therapeutics for brain diseases has remained challenging,in particular due to the difficulty of passing the blood-brain *** a result,the current arsenal of therapeutics targeting the brain is limited to small,lipid-soluble drugs and there is a lack of options for treating neuroblastomas,Alzheimer’s disease,and many other devastating *** the advances in strategies for crossing the blood-brain barrier such as the use of nanoparticles(Hersh et al.,2022;Duan et al.,2023),such delivery systems have not yet reached clinical ***,novel platforms for the transport of therapeutics across the blood-brain barrier remain highly *** specifically holds for large molecules such as monoclonal antibodies and recombinant proteins,as well as nucleotide-based therapeutics and cell *** efforts in this field are increasing exponentially,with thousands of publications in the last few years.

关键词： therapeutics holds spite

Modifying the progression of Parkinson's disease through movement interventions:multimodal quantification of underlying mechanisms

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Neural Regeneration Research 2024年第8期19卷 1651-1652页

作者： Manuel Bange Damian Marc Herz Dumitru Ciolac Gabriel Gonzalez-Escamilla Sergiu Groppa Section of Movement disorders and Neurostimulation Department of NeurologyFocus Program Translational Neuroscience(FTN)University Medical Center of the Johannes Gutenberg-University MainzMainzGermany

Introduction:Parkinson’s disease(PD)is the most common neurodegenerative movement *** pathological hallmark is the progressive loss of dopaminergic neurons of the substantia nigra pars compacta,which is accompanied by widespread alterations in the structu re and function of distributed brain *** r,these processes cause a variety of motor symptoms such as bradykinesia,rigidity,tremor,gait disorders,or difficulties in fine motor control(Bange et al.,2022).

关键词： alterations movement

Dysfunction of synaptic endocytic trafficking in Parkinson's disease

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Neural Regeneration Research 2024年第12期19卷 2649-2660页

作者： Xin Yi Ng Mian Cao programme in neuroscience and Behavioural disorders Duke-NUS Medical SchoolSingaporeSingapore Department of Physiology National University of SingaporeSingaporeSingapore

Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the *** precise reasons behind the specific degeneration of these dopamine neurons remain largely *** investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's ***,several of these genes are linked to the synaptic vesicle recycling process,particularly the clathrinmediated endocytosis *** suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease,followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a"dying back"***,several new animal and cellular models with Parkinson's disease-linked mutations affecting the endocytic pathway have been created and extensively *** models faithfully recapitulate certain Parkinson's disease-like features at the animal,circuit,and cellular levels,and exhibit defects in synaptic membrane trafficking,further supporting the findings from human genetics and clinical *** this review,we will first summarize the cellular and molecular findings from the models of two Parkinson's disease-linked clathrin uncoating proteins:auxilin(DNAJC6/PARK19)and synaptojanin 1(SYNJ1/PARK20).The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic ***,we will delve into the involvement of several clathrin-mediated endocytosis-related proteins(GAK,endophilin A1,SAC2/INPP5 F,synaptotagmin-11),identified as Parkinson's disease risk factors through genome-wide association studies,in Parkinson's disease *** will also explore the direct or indirect roles of some common Parkinson's disease-linked proteins(alpha-synuclein(PARK1/4),Parkin(PARK2),and LRRK2(PARK

关键词： autophagy auxilin/PARK19 clathrin-mediated endocytosis dopamine neurons neurodegeneration nigrostriatal pathway Parkinson's disease synaptic vesicle recycling synaptojanin1/PARK20

Polyethylene glycol fusion repair of severed sciatic nerves accelerates recovery of nociceptive sensory perceptions in male and female rats of different strains

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Neural Regeneration Research 2025年第09期 2667-2681页

作者： Liwen Zhou Karthik Venkudusamy Emily A.Hibbard Yessenia Montoya Alexa Olivarez Cathy Z.Yang Adelaide Leung Varun Gokhale Guhan Periyasamy Zeal Pathak Dale R.Sengelaub George D.Bittner Department of neuroscience University of Texas program in neuroscience Indiana University Department of Molecular Biosciences University of Texas

Successful polyethylene glycol fusion(PEG-fusion) of severed axons following peripheral nerve injuries for PEG-fused axons has been reported to:(1) rapidly restore electrophysiological continuity;(2) prevent distal Wallerian Degeneration and maintain their myelin sheaths;(3) promote primarily motor,voluntary behavioral recoveries as assessed by the Sciatic Functional Index;and,(4) rapidly produce correct and incorrect connections in many possible combinations that produce rapid and extensive recovery of functional peripheral nervous system/central nervous system connections and reflex(e.g.,toe twitch) or voluntary *** preceding companion paper describes sensory terminal field reo rganization following PEG-fusion repair of sciatic nerve transections or ablations;howeve r,sensory behavioral recovery has not been explicitly explored following PEG-fusion *** the current study,we confirmed the success of PEG-fusion surgeries according to criteria(1-3) above and more extensively investigated whether PEG-fusion enhanced mechanical nociceptive recovery following sciatic transection in male and female outbred Sprague-Dawley and inbred Lewis *** nociceptive responses were assessed by measuring withdrawal thresholds using von Frey filaments on the dorsal and midplantar regions of the *** von Frey filament tests were a more reliable method than plantar von Frey filament tests to assess mechanical nociceptive sensitivity following sciatic nerve *** withdrawal thresholds of the sciatic-mediated lateral dorsal region differed significantly across strain but not *** thresholds did not change significantly from baseline in chronic Unoperated and Sham-operated *** sciatic transection,all rats exhibited severe hyposensitivity to stimuli at the lateral dorsal region of the hindpaw ipsilateral to the ***,PEG-fused rats exhibited significantly earlier return to baseline withdrawal thresholds than N

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Polyethylene glycol fusion repair of severed sciatic nerves accelerates recovery of nociceptive sensory perceptions in male and female rats of different strains

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Neural Regeneration Research 2025年第9期20卷 2667-2681页

作者： Liwen Zhou Karthik Venkudusamy Emily A.Hibbard Yessenia Montoya Alexa Olivarez Cathy Z.Yang Adelaide Leung Varun Gokhale Guhan Periyasamy Zeal Pathak Dale R.Sengelaub George D.Bittner Department of neuroscience University of TexasAustinTXUSA program in neuroscience Indiana UniversityBloomingtonINUSA Department of Molecular Biosciences University of TexasAustinTXUSA

Successful polyethylene glycol fusion(PEG-fusion)of severed axons following peripheral nerve injuries for PEG-fused axons has been reported to:(1)rapidly restore electrophysiological continuity;(2)prevent distal Wallerian Degeneration and maintain their myelin sheaths;(3)promote primarily motor,voluntary behavioral recoveries as assessed by the Sciatic Functional Index;and,(4)rapidly produce correct and incorrect connections in many possible combinations that produce rapid and extensive recovery of functional peripheral nervous system/central nervous system connections and reflex(e.g.,toe twitch)or voluntary *** preceding companion paper describes sensory terminal field reo rganization following PEG-fusion repair of sciatic nerve transections or ablations;howeve r,sensory behavioral recovery has not been explicitly explored following PEG-fusion *** the current study,we confirmed the success of PEG-fusion surgeries according to criteria(1-3)above and more extensively investigated whether PEG-fusion enhanced mechanical nociceptive recovery following sciatic transection in male and female outbred Sprague-Dawley and inbred Lewis *** nociceptive responses were assessed by measuring withdrawal thresholds using von Frey filaments on the dorsal and midplantar regions of the *** von Frey filament tests were a more reliable method than plantar von Frey filament tests to assess mechanical nociceptive sensitivity following sciatic nerve *** withdrawal thresholds of the sciatic-mediated lateral dorsal region differed significantly across strain but not *** thresholds did not change significantly from baseline in chronic Unoperated and Sham-operated *** sciatic transection,all rats exhibited severe hyposensitivity to stimuli at the lateral dorsal region of the hindpaw ipsilateral to the ***,PEG-fused rats exhibited significantly earlier return to baseline withdrawal thresholds than Negative

关键词： autophagia axotomy collateral sprouting neuropathic pain peripheral nerve repair polyethylene glycol fusion(PEG-fusion) saphenous nerve sensory neurons sex and strain Wallerian degeneration

Polyethylene glycol fusion repair of severed rat sciatic nerves reestablishes axonal continuity and reorganizes sensory terminal fields in the spinal cord

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Neural Regeneration Research 2025年第7期20卷 2095-2107页

作者： Emily A.Hibbard Liwen Zhou Cathy Z.Yang Karthik Venkudusamy Yessenia Montoya Alexa Olivarez George D.Bittner Dale R.Sengelaub program in neuroscience Indiana UniversityBloomingtonINUSA Department of neuroscience University of Texas at AustinAustinTXUSA

Peripheral nerve injuries result in the rapid degeneration of distal nerve segments and immediate loss of motor and sensory functions;behavioral recovery is typically *** used a plasmalemmal fusogen,polyethylene glycol(PEG),to immediately fuse closely apposed open ends of severed proximal and distal axons in rat sciatic *** have previously reported that sciatic nerve axons repaired by PEG-fusion do not undergo Wallerian degeneration,and PEG-fused animals exhibit rapid(within 2–6 weeks)and extensive locomotor ***,our previous report showed that PEG-fusion of severed sciatic motor axons was non-specific,i.e.,spinal motoneurons in PEG-fused animals were found to project to appropriate as well as inappropriate target *** this study,we examined the consequences of PEG-fusion for sensory axons of the sciatic *** adult male and female rats(Sprague–Dawley)received either a unilateral single cut or ablation injury to the sciatic nerve and subsequent repair with or without(Negative Control)the application of *** action potentials recorded immediately after PEG-fusion repair confirmed conduction across the injury *** success of PEG-fusion was confirmed through Sciatic Functional Index testing with PEG-fused animals showing improvement in locomotor function beginning at 35 days *** 2–42 days postoperatively,we anterogradely labeled sensory afferents from the dorsal aspect of the hindpaw following bilateral intradermal injection of wheat germ agglutinin conjugated horseradish ***-fusion repair reestablished axonal *** to unoperated animals,labeled sensory afferents ipsilateral to the injury in PEG-fused animals were found in the appropriate area of the dorsal horn,as well as inappropriate mediolateral and rostrocaudal ***,despite having intact peripheral nerves,similar reorganizations of labeled sensory afferents were also observed contralateral to the injury and repa

关键词： axotomy dorsal horn peripheral nerve injury plasticity polyethylene glycol(PEG) sciatic nerve sensory terminals wheat germ agglutinin horseradish peroxidase

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

The physiological role of the unfolded protein response in the nervous system

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Neural Regeneration Research 2024年第11期19卷 2411-2420页

作者： Shuangchan Wu Wensheng Lin Department of neuroscience University of MinnesotaMinneapolisMNUSA Institute for Translational neuroscience University of MinnesotaMinneapolisMNUSA

The unfolded protein response(UPR)is a cellular stress response pathway activated when the endoplasmic reticulum,a crucial organelle for protein folding and modification,encounters an accumulation of unfolded or misfolded *** UPR aims to restore endoplasmic reticulum homeostasis by enhancing protein folding capacity,reducing protein biosynthesis,and promoting protein *** also plays a pivotal role in coordinating signaling cascades to determine cell fate and function in response to endoplasmic reticulum *** research has highlighted the significance of the UPR not only in maintaining endoplasmic reticulum homeostasis but also in influencing various physiological processes in the nervous ***,we provide an overview of recent findings that underscore the UPR’s involvement in preserving the function and viability of neuronal and myelinating cells under physiological conditions,and highlight the critical role of the UPR in brain development,memory storage,retinal cone development,myelination,and maintenance of myelin thickness.

关键词： myelin neuron oligodendrocyte Schwann cell unfolded protein response