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Targeting cell surface receptors for axon regeneration in the central nervous system

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Neural Regeneration Research 2016年第12期11卷 1884-1887页

作者： Menghon Cheah Melissa R.Andrews John van Geest centre for brain repair University of Cambridge School of Medicine University of St.Andrews

Axon regeneration in the CNS is largely unsuccessful due to excess inhibitory extrinsic factors within lesion sites together with an intrinsic inability of neurons to regrow following injury. Recent work demonstrates that forced expression of certain neuronal transmembrane receptors can recapitulate neuronal growth resulting in successful growth within and through inhibitory lesion environments. More specifically, neuronal expression of integrin receptors such as alpha9beta1 integrin which binds the extracellular matrix glycoprotein tenascin-C, trk receptors such as trk B which binds the neurotrophic factor BDNF, and receptor PTPσ which binds chondroitin sulphate proteoglycans, have all been show to significantly enhance regeneration of injured axons. We discuss how reintroduction of these receptors in damaged neurons facilitates signalling from the internal environment of the cell with the external environment of the lesion milieu, effectively resulting in growth and repair following injury. In summary, we suggest an appropriate balance of intrinsic and extrinsic factors are required to obtain substantial axon regeneration.

关键词： axon regeneration dorsal root ganglion extracellular matrix integrin tenascin-c trk receptors

Promoting axon regeneration in the central nervous system by increasing PI3-kinase signaling

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Neural Regeneration Research 2022年第6期17卷 1172-1182页

作者： Bart Nieuwenhuis Richard Eva John van Geest Center for brain repair Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK

Much research has focused on the PI3-kinase and PTEN signaling pathway with the aim to stimulate repair of the injured central nervous *** in the central nervous system fail to regenerate,meaning that injuries or diseases that cause loss of axonal connectivity have life-changing *** 2008,genetic deletion of PTEN was identified as a means of stimulating robust regeneration in the optic *** is a phosphatase that opposes the actions of PI3-kinase,a family of enzymes that function to generate the membrane phospholipid PIP_(3) from PIP_(2)(phosphatidylinositol(3,4,5)-trisphosphate from phosphatidylinositol(4,5)-bisphosphate).Deletion of PTEN therefore allows elevated signaling downstream of PI3-kinase,and was initially demonstrated to promote axon regeneration by signaling through *** recently,additional mechanisms have been identified that contribute to the neuron-intrinsic control of regenerative *** review describes neuronal signaling pathways downstream of PI3-kinase and PIP3,and considers them in relation to both developmental and regenerative axon *** briefly discuss the key neuron-intrinsic mechanisms that govern regenerative ability,and describe how these are affected by signaling through *** highlight the recent finding of a developmental decline in the generation of PIP_(3) as a key reason for regenerative failure,and summarize the studies that target an increase in signaling downstream of PI3-kinase to facilitate regeneration in the adult central nervous ***,we discuss obstacles that remain to be overcome in order to generate a robust strategy for repairing the injured central nervous system through manipulation of PI3-kinase signaling.

关键词： axon cytoskeleton axon regeneration axon transport cell signaling central nervous system growth cone neuroprotection PI3-kinase PI3K PTEN trafficking transcription translation

Emergence of the Wallerian degeneration pathway as a mechanism of secondary brain injury

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Neural Regeneration Research 2021年第5期16卷 980-981页

作者： Ciaran Scott Hill Andrea Loreto National Hospital for Neurology and Neurosurgery University College London HospitalsUCL Cancer InstituteUniversity College LondonLondonUK Jon Van Geest centre for brain repair University of CambridgeCambridgeUK

Augustus Volney Wal ler was a renowned British neurophysiologist who birthed the axon degeneration field in 1850 by describing curdling and fragmentation of the glossopharyngeal and hypoglossal cranial nerves of a frog following a transection *** degeneration of axons after a transection injury is now known as Wallerian degeneration(WD).Waller’s work was expanded by Santiago Ramón y Cajal who described in detail the morphological stages of WD from monitory fragmentation of the axon and the granular disintegration of the neurofibrils to the final resorption of the axon.

关键词： degeneration nerves Wallerian

State-of-art modelling of inflammatory astrocyte-synapse interactions in injury and amyotrophic lateral sclerosis

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Neural Regeneration Research 2017年第1期12卷 75-76页

作者： András Lakatos John van Geest centre for brain repair Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUnited Kingdom Department of Neurology Addenbrooke's HospitalCambridge University Hospitals NHS TrustCambridgeUnited Kingdom

Different outcomes of astrocyte inflammatory signalling in injury and neurodegeneration：It is emerging that astrocytes have a significant impact on the neuronal network by modulating synaptic connections and neuronal... 详细信息

关键词： astrocyte amyotrophic neuronal synaptic modulating insight viability glutamate inflammation NMDAR

Linking axon transport to regeneration using in vitro laser axotomy

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Neural Regeneration Research 2018年第3期13卷 410-412页

作者： Bart Nieuwenhuis Richard Eva John van Geest centre for brain repair Department of Clinical Neurosciences University of Cambridge Cambridge UK Laboratory for Regeneration of Sensorimotor Systems Netherlands Institute for Neuroscience Royal Netherlands Academy of Arts and Sciences (KNAW) Amsterdam The Netherlands

Spinal cord injury has devastating consequences because adult central nervous system （CNS） neurons do not regenerate their axons after injury. Two key reasons for axon regeneration fail- ure are extrinsic inhibitory factors and a low intrinsic capacity for axon regrowth. Research has therefore focused on overcom- ing extrinsic growth inhibition, and enhancing intrinsic regeneration capacity. Both of these issues will need to be addressed to enable optimal repair of the injured sp＋inal cord.

关键词： CNS ARF Linking axon transport to regeneration using in vitro laser axotomy EFA

Neural grafting for Parkinson's disease:challenges and prospects

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Neural Regeneration Research 2017年第3期12卷 389-392页

作者： Thomas B.Stoker Nicholas F.Blair Roger A.Barker John van Geest Center for brain repair Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK Wellcome Trust-Medical Research Council Stem Cell Institute University of CambridgeCambridgeUK

Parkinson＇s disease（PD） is a neurodegenerative condition which causes a characteristic movement disorder secondary to loss of dopaminergic neurons in the substanitia *** motor disorder responds well to dopamine-replacement therapies,though these result in significant adverse effects due to non-physiological release of dopamine in the striatum,and off-target ***-based regenerative treatments offer a potential means for targeted replacement of dopamine,in a physiological *** neurons for cell-based therapies can be obtained from several *** ventral mesencephalon tissue contains dopaminergic neuron progenitors,and has been transplanted into the striatum of PD patients with good results in a number of ***,the ethical implications and logistical challenges of using fetal tissue mean that fetal ventral mesencephalon is unlikely to be used in a widespread clinical *** pluripotent stem cells can be used to generate dopaminergic neurons for transplantation,providing a source of autologous tissue for *** approach means that challenges associated with allografts,such as the potential for immune rejection,can be ***,the associated cost and difficulty in producing a standardized product from different cell lines means that,at present,this approach is not commercially viable as a cell-based *** neurons derived from embryonic stem cells offer the most promising basis for a cell-based therapy for Parkinson＇s disease,with trials due to commence in the next few *** there are ethical considerations to take into account when using embryonic tissue,the possibility of producing a standardized,optimized cell product means that this approach can be both effective,and commercially viable.

关键词： Parkinson's disease neural grafting embryonic stem cells induced pluripotent stem cells induced neurons cell-based therapies

Trick or treat?Does cancer fool Schwann cells by mimicking axons to promote metastasis into nerves?

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Neural Regeneration Research 2023年第8期18卷 1727-1727页

作者： Peter Arthur-Farraj John Van Geest centre for brain repair Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK

The Schwann cell reaction to nerve injury,termed the repair program,is crucial to successful nerve *** the last decade,substantial advances have been made in elucidating the underlying molecular mechanisms in Schwann cells that lead to functional nerve ***,the field has identified situations,such as aging and chronic denervation where these mechanisms go awry,paving the way for the development of therapeutic interventions(Arthur-Farraj and Coleman,2021;Cattin and Lloyd,2016;Jessen and Mirsky,2019).A recent article by Deborde et al.(2022)has demonstrated that unfortunately there is a downside to Schwann cells having such an efficient regeneration-promoting program;the promotion of tumor invasion of peripheral nerves.

关键词： nerves invasion metastasis

Neuro-oncogenesis and the adult human sub-ventricular zone in high grade glioma

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Neuroimmunology and Neuroinflammation 2016年第1期3卷 20-26页

作者： Sara G.M.Piccirillo John van Geest centre for brain repair Department of Clinical NeurosciencesUniversity of CambridgeCambridgeCB20PYUK

The last fifteen years have seen the application of the cancer stem cell hypothesis to tumors of the central nervous system,in particular to high grade glioma(HGG),the most aggressive and common brain cancer in *** studies have shown that cancer stem cells(alternatively named tumor-initiating cells)are capable of self-renew and multipotency,similar to their normal *** importantly they give rise to tumors that closely mimic the phenotype and genotype of human *** identification of neurogenic niches in adult rodent and human brain has further reinforced the hypothesis that HGG might derive from the malignant transformation occurring in these areas,especially in the sub-ventricular zone(SVZ),the largest and most well characterised stem cell *** from evidence of animal model studies supporting this hypothesis,recently we investigated the role of the SVZ in neuro-oncogenesis using tissue material derived from HGG *** also described response to conventional chemo-therapies of cancer stem cells isolated from the SVZ and the tumor mass(T)of the same patients and reconstructed tumor *** this review,such findings will be discussed in the context of the current literature on the biology of the SVZ in the normal and disease brain.

关键词： High grade glioma tumor-initiating cells sub-ventricular zone tumor development

Targeting Wnt signaling at the neuroimmune interface for dopaminergic neuroprotectionJrepair in Parkinson＇s disease

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Journal of Molecular Cell Biology 2014年第1期8卷 13-26页

作者： Francesca L'Episcopo Cataldo Tirolo Salvo Caniglia Nuccio Testa Maria Concetta Moral~ Maria Francesca Serapide: Stefano Pluchino Bianca Marchetti OASI Institute for Research and Care on Mental Retardation and brain Aging (IRCCS) Neuropharmacology Section Via Conte Ruggero 73 94018 Troina Italy Department of Physiolocal Sciences Medical School University of Catania Viale A. Doria 6 95125 Catania Italy Department of Clinical Neurosciences John van Geest Centre for Brain Repair and Wellcome Trust-Medical Research Counci~ Stem Celt Institute University ofCambridge Cambridge CB20PY UK Department of Clinical and Molecular Biomedicine Pharmacology Section Medical School University of Catania Viale A. Doria 6 95125 Catania Italy

During the past three decades, the Wingless-type MMTV integration site （Wnt） signaling cascade has emerged as an essential system regulating multiple processes in developing and adult brain. Accumulating evidence points to a dysregulation of Wnt signaling in major neurodegenerative pathologies including Parkinson＇s disease （PD）, a common neurodegenerative disorder characterized by the pro- gressive loss of midbrain dopaminergic （mDA） neurons and deregulated activation of astrocytes and microglia. This review highlights the emerging link between Wnt signaling and key inflammatory pathways during mDA neuron damage/repair in PD progression. In particular, we summarize recent evidence documenting that aging and neurotoxicant exposure strongly antagonize Wnt/β-catenin signaling in mDA neurons and subventricular zone （SVZ） neuroprogenitors via astrocyte-microglial interactions. Dysregulation of the crosstalk between Wnt/β-catenin signaling and anti-oxidant/anti-inflammatory pathways delineate novel mechanisms driving the decline of SVZ plasticity with age and the limited nigrostriatal dopaminergic self-repair in PD. These findings hold a promise in devetoping therapies that target Wnt/β-catenin signaling to enhance endogenous restoration and neuronal outcome in age-dependent diseases, such as PD.

关键词： Wnt/β-catenin signaling Parkinson's disease neuroinflammation dopaminergic neurons neurogenesis neurodegeneration neuroprotection