dc.contributor.author | Wali, Gautam | |
dc.contributor.author | Sutharsan, Ratneswary | |
dc.contributor.author | Fan, Yongjun | |
dc.contributor.author | Stewart, Romal | |
dc.contributor.author | Velasquez, Johana Tello | |
dc.contributor.author | Sue, Carolyn M | |
dc.contributor.author | Crane, Denis I | |
dc.contributor.author | Mackay-Sim, Alan | |
dc.date.accessioned | 2017-11-23T03:58:48Z | |
dc.date.available | 2017-11-23T03:58:48Z | |
dc.date.issued | 2016 | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.doi | 10.1038/srep27004 | |
dc.identifier.uri | http://hdl.handle.net/10072/100666 | |
dc.description.abstract | Hereditary 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.peerreviewed | Yes | |
dc.language | English | |
dc.language.iso | eng | |
dc.publisher | Nature Macmillan | |
dc.relation.ispartofpagefrom | 27004-1 | |
dc.relation.ispartofpageto | 27004-14 | |
dc.relation.ispartofjournal | Scientific Reports | |
dc.relation.ispartofvolume | 6 | |
dc.subject.fieldofresearch | Biochemistry and cell biology not elsewhere classified | |
dc.subject.fieldofresearchcode | 310199 | |
dc.title | Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dc.type.code | C - Journal Articles | |
dcterms.license | http://creativecommons.org/licenses/by/4.0/ | |
dc.description.version | Version of Record (VoR) | |
gro.faculty | Griffith 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.hasfulltext | Full Text | |
gro.griffith.author | Crane, Denis I. | |
gro.griffith.author | Mackay-Sim, Alan | |