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Mild and repetitive very mild axonal stretch injury triggers cystoskeletal mislocalization and growth cone collapse

Yap, Yiing C, King, Anna E, Guijt, Rosanne M., Jiang, Tongcui, Blizzard, Catherine A, Breadmore, Michael C and Dickson, Tracey C 2017, Mild and repetitive very mild axonal stretch injury triggers cystoskeletal mislocalization and growth cone collapse, PLoS One, vol. 12, no. 5, pp. 1-19, doi: 10.1371/journal.pone.0176997.

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Title Mild and repetitive very mild axonal stretch injury triggers cystoskeletal mislocalization and growth cone collapse
Author(s) Yap, Yiing C
King, Anna E
Guijt, Rosanne M.ORCID iD for Guijt, Rosanne M. orcid.org/0000-0003-0011-5708
Jiang, Tongcui
Blizzard, Catherine A
Breadmore, Michael C
Dickson, Tracey C
Journal name PLoS One
Volume number 12
Issue number 5
Article ID e0176997
Start page 1
End page 19
Total pages 19
Publisher Public Library of Science
Place of publication San Franciso, Calif.
Publication date 2017
ISSN 1932-6203
Keyword(s) Axons
Cells, Cultured
Cytoskeleton
Diffuse Axonal Injury
Growth Cones
Humans
In Vitro Techniques
Microfluidics
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
TRAUMATIC BRAIN-INJURY
TRANSGENIC MOUSE MODEL
IN-VITRO
COGNITIVE IMPAIRMENT
SOFT LITHOGRAPHY
PHYSICAL INJURY
HEAD-INJURY
DEGENERATION
MICROTUBULES
REGENERATION
Summary Diffuse axonal injury is a hallmark pathological consequence of non-penetrative traumatic brain injury (TBI) and yet the axonal responses to stretch injury are not fully understood at the cellular level. Here, we investigated the effects of mild (5%), very mild (0.5%) and repetitive very mild (2×0.5%) axonal stretch injury on primary cortical neurons using a recently developed compartmentalized in vitro model. We found that very mild and mild levels of stretch injury resulted in the formation of smaller growth cones at the tips of axons and a significantly higher number of collapsed structures compared to those present in uninjured cultures, when measured at both 24 h and 72 h post injury. Immunocytochemistry studies revealed that at 72 h following mild injury the axonal growth cones had a significantly higher colocalization of βIII tubulin and F-actin and higher percentage of collapsed morphology than those present following a very mild injury. Interestingly, cultures that received a second very mild stretch injury, 24 h after the first insult, had a further increased proportion of growth cone collapse and increased βIII tubulin and F-actin colocalization, compared with a single very mild injury at 72 h PI. In addition, our results demonstrated that microtubule stabilization of axons using brain penetrant Epothilone D (EpoD) (100 nM) resulted in a significant reduction in the number of fragmented axons following mild injury. Collectively, these results suggest that mild and very mild stretch injury to a very localized region of the cortical axon is able to trigger a degenerative response characterized by growth cone collapse and significant abnormal cytoskeletal rearrangement. Furthermore, repetitive very mild stretch injury significantly exacerbated this response. Results suggest that axonal degeneration following stretch injury involves destabilization of the microtubule cytoskeleton and hence treatment with EpoD reduced fragmentation. Together, these results contribute a better understanding of the pathogenesis of mild and repetitive TBI and highlight the therapeutic effect of microtubule targeted drugs on distal part of neurons using a compartmentalized culturing model.
Language eng
DOI 10.1371/journal.pone.0176997
Field of Research MD Multidisciplinary
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2017, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30109945

Document type: Journal Article
Collections: School of Life and Environmental Sciences
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.