Intravitreal application of AAV-BDNF or mutant AAV-CRMP2 protects retinal ganglion cells and stabilizes axons and myelin after partial optic nerve injury
© 2020 Elsevier Inc. Secondary degeneration following an initial injury to the central nervous system (CNS) results in increased tissue loss and is associated with increasing functional impairment. Unilateral partial dorsal transection of the adult rat optic nerve (ON) has proved to be a useful expe...
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| Format: | Journal Article |
| Language: | English |
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ACADEMIC PRESS INC ELSEVIER SCIENCE
2020
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| Online Access: | http://purl.org/au-research/grants/nhmrc/1087114 http://hdl.handle.net/20.500.11937/81493 |
| _version_ | 1848764377348440064 |
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| author | Chiha, Wissam Bartlett, C.A. Petratos, S. Fitzgerald, Melinda Harvey, A.R. |
| author_facet | Chiha, Wissam Bartlett, C.A. Petratos, S. Fitzgerald, Melinda Harvey, A.R. |
| author_sort | Chiha, Wissam |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | © 2020 Elsevier Inc. Secondary degeneration following an initial injury to the central nervous system (CNS) results in increased tissue loss and is associated with increasing functional impairment. Unilateral partial dorsal transection of the adult rat optic nerve (ON) has proved to be a useful experimental model in which to study factors that contribute to secondary degenerative events. Using this injury model, we here quantified the protective effects of intravitreally administered bi-cistronic adeno-associated viral (AAV2) vectors encoding either brain derived neurotrophic factor (BDNF) or a mutant, phospho-resistant, version of collapsin response mediator protein 2 (CRMP2T555A) on retinal ganglion cells (RGCs), their axons, and associated myelin. To test for potential synergistic interactions, some animals received combined injections of both vectors. Three months post-injury, all treatments maintained RGC numbers in central retina, but only AAV2-BDNF significantly protected ventrally located RGCs exclusively vulnerable to secondary degeneration. Behaviourally, treatments that involved AAV2-BDNF significantly restored the number of smooth-pursuit phases of optokinetic nystagmus. While all therapeutic regimens preserved axonal density and proportions of typical complexes, including heminodes and single nodes, BDNF treatments were generally more effective in maintaining the length of the node of Ranvier in myelin surrounding ventral ON axons after injury. Both AAV2-BDNF and AAV2-CRMP2T555A prevented injury-induced changes in G-ratio and overall myelin thickness, but only AAV2-BDNF administration protected against large-scale myelin decompaction in ventral ON. In summary, in a model of secondary CNS degeneration, both BDNF and CRMP2T555A vectors were neuroprotective, however different efficacies were observed for these overexpressed proteins in the retina and ON, suggesting disparate cellular and molecular targets driving responses for neural repair. The potential use of these vectors to treat other CNS injuries and pathologies is discussed. |
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| format | Journal Article |
| id | curtin-20.500.11937-81493 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T11:18:23Z |
| publishDate | 2020 |
| publisher | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| recordtype | eprints |
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| spelling | curtin-20.500.11937-814932021-01-06T05:13:28Z Intravitreal application of AAV-BDNF or mutant AAV-CRMP2 protects retinal ganglion cells and stabilizes axons and myelin after partial optic nerve injury Chiha, Wissam Bartlett, C.A. Petratos, S. Fitzgerald, Melinda Harvey, A.R. Science & Technology Life Sciences & Biomedicine Neurosciences Neurosciences & Neurology Secondary degeneration Collapsin response mediator protein 2 Brain derived neurotrophic factor Retinal ganglion cells Adeno-associated viral vector Gene therapy CHRONIC SECONDARY DEGENERATION NEUROTROPHIC FACTOR GENE-THERAPY TRANSGENE EXPRESSION CONDUCTION-VELOCITY ACTION-POTENTIALS GROWTH-FACTOR CNS NEURONS TIME-COURSE ADULT-RATS © 2020 Elsevier Inc. Secondary degeneration following an initial injury to the central nervous system (CNS) results in increased tissue loss and is associated with increasing functional impairment. Unilateral partial dorsal transection of the adult rat optic nerve (ON) has proved to be a useful experimental model in which to study factors that contribute to secondary degenerative events. Using this injury model, we here quantified the protective effects of intravitreally administered bi-cistronic adeno-associated viral (AAV2) vectors encoding either brain derived neurotrophic factor (BDNF) or a mutant, phospho-resistant, version of collapsin response mediator protein 2 (CRMP2T555A) on retinal ganglion cells (RGCs), their axons, and associated myelin. To test for potential synergistic interactions, some animals received combined injections of both vectors. Three months post-injury, all treatments maintained RGC numbers in central retina, but only AAV2-BDNF significantly protected ventrally located RGCs exclusively vulnerable to secondary degeneration. Behaviourally, treatments that involved AAV2-BDNF significantly restored the number of smooth-pursuit phases of optokinetic nystagmus. While all therapeutic regimens preserved axonal density and proportions of typical complexes, including heminodes and single nodes, BDNF treatments were generally more effective in maintaining the length of the node of Ranvier in myelin surrounding ventral ON axons after injury. Both AAV2-BDNF and AAV2-CRMP2T555A prevented injury-induced changes in G-ratio and overall myelin thickness, but only AAV2-BDNF administration protected against large-scale myelin decompaction in ventral ON. In summary, in a model of secondary CNS degeneration, both BDNF and CRMP2T555A vectors were neuroprotective, however different efficacies were observed for these overexpressed proteins in the retina and ON, suggesting disparate cellular and molecular targets driving responses for neural repair. The potential use of these vectors to treat other CNS injuries and pathologies is discussed. 2020 Journal Article http://hdl.handle.net/20.500.11937/81493 10.1016/j.expneurol.2019.113167 English http://purl.org/au-research/grants/nhmrc/1087114 http://creativecommons.org/licenses/by-nc-nd/4.0/ ACADEMIC PRESS INC ELSEVIER SCIENCE fulltext |
| spellingShingle | Science & Technology Life Sciences & Biomedicine Neurosciences Neurosciences & Neurology Secondary degeneration Collapsin response mediator protein 2 Brain derived neurotrophic factor Retinal ganglion cells Adeno-associated viral vector Gene therapy CHRONIC SECONDARY DEGENERATION NEUROTROPHIC FACTOR GENE-THERAPY TRANSGENE EXPRESSION CONDUCTION-VELOCITY ACTION-POTENTIALS GROWTH-FACTOR CNS NEURONS TIME-COURSE ADULT-RATS Chiha, Wissam Bartlett, C.A. Petratos, S. Fitzgerald, Melinda Harvey, A.R. Intravitreal application of AAV-BDNF or mutant AAV-CRMP2 protects retinal ganglion cells and stabilizes axons and myelin after partial optic nerve injury |
| title | Intravitreal application of AAV-BDNF or mutant AAV-CRMP2 protects retinal ganglion cells and stabilizes axons and myelin after partial optic nerve injury |
| title_full | Intravitreal application of AAV-BDNF or mutant AAV-CRMP2 protects retinal ganglion cells and stabilizes axons and myelin after partial optic nerve injury |
| title_fullStr | Intravitreal application of AAV-BDNF or mutant AAV-CRMP2 protects retinal ganglion cells and stabilizes axons and myelin after partial optic nerve injury |
| title_full_unstemmed | Intravitreal application of AAV-BDNF or mutant AAV-CRMP2 protects retinal ganglion cells and stabilizes axons and myelin after partial optic nerve injury |
| title_short | Intravitreal application of AAV-BDNF or mutant AAV-CRMP2 protects retinal ganglion cells and stabilizes axons and myelin after partial optic nerve injury |
| title_sort | intravitreal application of aav-bdnf or mutant aav-crmp2 protects retinal ganglion cells and stabilizes axons and myelin after partial optic nerve injury |
| topic | Science & Technology Life Sciences & Biomedicine Neurosciences Neurosciences & Neurology Secondary degeneration Collapsin response mediator protein 2 Brain derived neurotrophic factor Retinal ganglion cells Adeno-associated viral vector Gene therapy CHRONIC SECONDARY DEGENERATION NEUROTROPHIC FACTOR GENE-THERAPY TRANSGENE EXPRESSION CONDUCTION-VELOCITY ACTION-POTENTIALS GROWTH-FACTOR CNS NEURONS TIME-COURSE ADULT-RATS |
| url | http://purl.org/au-research/grants/nhmrc/1087114 http://hdl.handle.net/20.500.11937/81493 |