Show simple item record

dc.contributor.authorWali, Gautam
dc.contributor.authorSutharsan, Ratneswary
dc.contributor.authorFan, Yongjun
dc.contributor.authorStewart, Romal
dc.contributor.authorVelasquez, Johana Tello
dc.contributor.authorSue, Carolyn M
dc.contributor.authorCrane, Denis I
dc.contributor.authorMackay-Sim, Alan
dc.date.accessioned2017-11-23T03:58:48Z
dc.date.available2017-11-23T03:58:48Z
dc.date.issued2016
dc.identifier.issn2045-2322
dc.identifier.doi10.1038/srep27004
dc.identifier.urihttp://hdl.handle.net/10072/100666
dc.description.abstractHereditary spastic paraplegia (HSP) is an inherited neurological condition that leads to progressive spasticity and gait abnormalities. Adult-onset HSP is most commonly caused by mutations in SPAST, which encodes spastin a microtubule severing protein. In olfactory stem cell lines derived from patients carrying different SPAST mutations, we investigated microtubule-dependent peroxisome movement with time-lapse imaging and automated image analysis. The average speed of peroxisomes in patient-cells was slower, with fewer fast moving peroxisomes than in cells from healthy controls. This was not because of impairment of peroxisome-microtubule interactions because the time-dependent saltatory dynamics of movement of individual peroxisomes was unaffected in patient-cells. Our observations indicate that average peroxisome speeds are less in patient-cells because of the lower probability of individual peroxisome interactions with the reduced numbers of stable microtubules: peroxisome speeds in patient cells are restored by epothilone D, a tubulin-binding drug that increases the number of stable microtubules to control levels. Patient-cells were under increased oxidative stress and were more sensitive than control-cells to hydrogen peroxide, which is primarily metabolised by peroxisomal catalase. Epothilone D also ameliorated patient-cell sensitivity to hydrogen-peroxide. Our findings suggest a mechanism for neurodegeneration whereby SPAST mutations indirectly lead to impaired peroxisome transport and oxidative stress.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherNature Macmillan
dc.relation.ispartofpagefrom27004-1
dc.relation.ispartofpageto27004-14
dc.relation.ispartofjournalScientific Reports
dc.relation.ispartofvolume6
dc.subject.fieldofresearchBiochemistry and cell biology not elsewhere classified
dc.subject.fieldofresearchcode310199
dc.titleMechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/
dc.description.versionVersion of Record (VoR)
gro.facultyGriffith Sciences, Griffith Institute for Drug Discovery
gro.rights.copyright© The Author(s) 2016. This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorCrane, Denis I.
gro.griffith.authorMackay-Sim, Alan


Files in this item

This item appears in the following Collection(s)

  • Journal articles
    Contains articles published by Griffith authors in scholarly journals.

Show simple item record