For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
100
views
33
references
 Top references
cited by
51
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    4
    shares
      440
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: not found

      Focal Transplantation-based Astrocyte Replacement is Neuroprotective in a Model of Motor Neuron Disease

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Cellular abnormalities in amyotrophic lateral sclerosis (ALS) are not limited to motor neurons. Astrocyte dysfunction occurs in human ALS and SOD1 G93A animal models. Therefore, the value of focal enrichment of normal astrocytes was investigated using transplantation of lineage-restricted astrocyte precursors, Glial-Restricted Precursors (GRPs). GRPs were transplanted around cervical spinal cord respiratory motor neuron pools, the principal cells responsible for death in this neurodegenerative disease. GRPs survived in diseased tissue, differentiated efficiently into astrocytes, and reduced microgliosis in SOD1 G93A rat cervical spinal cord. GRPs extended survival and disease duration, attenuated motor neuron loss, and slowed declines in fore-limb motor and respiratory physiological function. Neuroprotection was mediated in part by the primary astrocyte glutamate transporter, GLT1. These findings demonstrate the feasibility and efficacy of transplantation-based astrocyte replacement, and show that targeted multi-segmental cell delivery to cervical spinal cord is a promising therapeutic strategy for slowing focal motor neuron loss associated with ALS.

          Related collections

          Most cited references33

          • Record: found
          • Abstract: found
          • Article: not found

          Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.

          M. Gurney, H. Pu, A Chiu … (1994)
          Mutations of human Cu,Zn superoxide dismutase (SOD) are found in about 20 percent of patients with familial amyotrophic lateral sclerosis (ALS). Expression of high levels of human SOD containing a substitution of glycine to alanine at position 93--a change that has little effect on enzyme activity--caused motor neuron disease in transgenic mice. The mice became paralyzed in one or more limbs as a result of motor neuron loss from the spinal cord and died by 5 to 6 months of age. The results show that dominant, gain-of-function mutations in SOD contribute to the pathogenesis of familial ALS.
          Article 0 comments Cited 452 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression.

            Jeffrey Rothstein, Sarjubhai Patel, Melissa R Regan … (2005)
            Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many beta-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene. beta-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways. When delivered to animals, the beta-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity. When used in an animal model of the fatal disease ALS, the drug delayed loss of neurons and muscle strength, and increased mouse survival. Thus these studies provide a class of potential neurotherapeutics that act to modulate the expression of glutamate neurotransmitter transporters via gene activation.
            Article 0 comments Cited 280 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Unraveling the mechanisms involved in motor neuron degeneration in ALS.

              Lucie I Bruijn, Timothy Miller, Don Cleveland (2004)
              Although Charcot described amyotrophic lateral sclerosis (ALS) more than 130 years ago, the mechanism underlying the characteristic selective degeneration and death of motor neurons in this common adult motor neuron disease has remained a mystery. There is no effective remedy for this progressive, fatal disorder. Modern genetics has now identified mutations in one gene [Cu/Zn superoxide dismutase (SOD1)] as a primary cause and implicated others [encoding neurofilaments, cytoplasmic dynein and its processivity factor dynactin, and vascular endothelial growth factor (VEGF)] as contributors to, or causes of, motor neuron diseases. These insights have enabled development of model systems to test hypotheses of disease mechanism and potential therapies. Along with errors in the handling of synaptic glutamate and the potential excitotoxic response this provokes, these model systems highlight the involvement of nonneuronal cells in disease progression and provide new therapeutic strategies.
              Article 0 comments Cited 267 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9809671
                Journal ID (pubmed-jr-id): 21092
                Journal ID (nlm-ta): Nat Neurosci
                Title: Nature neuroscience
                ISSN (Print): 1097-6256
                ISSN (Electronic): 1546-1726
                Publication date Nihms-submitted: 23 September 2008
                Publication date (Electronic): 19 October 2008
                Publication date (Print): November 2008
                Publication date PMC-release: 1 May 2009
                Volume: 11
                Issue: 11
                Pages: 1294-1301
                Affiliations
                [1 ]Department of Neurology, The Johns Hopkins University School of Medicine, 600 N. Wolfe St., Meyer 6-109, Baltimore, MD 21287
                [2 ]Department of Neuroscience, The Johns Hopkins University School of Medicine, 600 N. Wolfe St., Meyer 6-109, Baltimore, MD 21287
                [3 ]Invitrogen Corporation, 1610 Faraday Ave, Carlsbad, CA 92008
                Author notes
                [4 ]To whom correspondence should be addressed: Nicholas J. Maragakis, M.D., Department of Neurology, The Johns Hopkins School of Medicine, 600 North Wolfe Street, Meyer 6-119, Baltimore, MD 21287, Phone: 410-614-9874, Fax: 443-287-3933, E-mail: nmaragak@ 123456jhmi.edu

                Author Contributions

                A.C.L. designed and conducted the experiments, analyzed the data, prepared the figures, and wrote the manuscript. N.J.M. supervised the project, and participated in designing experiments and writing the manuscript. M.S.R. and J.D.R. participated in designing experiments and writing the manuscript. B.R., A.C.P. and C.D. conducted experiments.

                Article
                Manuscript ID: nihpa69830
                DOI: 10.1038/nn.2210
                PMC ID: 2656686
                PubMed ID: 18931666
                SO-VID: 89cc9230-a323-4ccb-a296-b87d749ab1ce
                History
                Funding
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: R01 NS041680-05 ||NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: R01 NS033958-13 ||NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: F32 NS059155-01A1 ||NS
                Categories
                Subject: Article

                ScienceOpen disciplines: Neurosciences
                Keywords: amyotrophic lateral sclerosis,sod1,neuroprotection,transplantation,progenitor,neurodegeneration,neural precursor cell,grafting,motor neuron,non-cell autonomous,stem cell,astroglia,astrocyte,replacement,glial precursor,als,lineage-restricted precursor
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: amyotrophic lateral sclerosis, sod1, neuroprotection, transplantation, progenitor, neurodegeneration, neural precursor cell, grafting, motor neuron, non-cell autonomous, stem cell, astroglia, astrocyte, replacement, glial precursor, als, lineage-restricted precursor

                Comments

                Comment on this article

                scite_

                Similar content440

                See all similar

                Cited by127

                See all cited by

                Most referenced authors1,018

                See all reference authors