Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia

Wali, Gautam, Sutharsan, Ratneswary, Fan, Yongjun, Stewart, Romal, Velasquez, Johana Tello, Sue, Carolyn M., Crane, Denis I. and Mackay-Sim, Alan (2016) Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia. Scientific Reports, 6 27004: 1-14. doi:10.1038/srep27004


Author Wali, Gautam
Sutharsan, Ratneswary
Fan, Yongjun
Stewart, Romal
Velasquez, Johana Tello
Sue, Carolyn M.
Crane, Denis I.
Mackay-Sim, Alan
Title Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia
Journal name Scientific Reports   Check publisher's open access policy
ISSN 2045-2322
Publication date 2016-05-27
Year available 2016
Sub-type Article (original research)
DOI 10.1038/srep27004
Open Access Status DOI
Volume 6
Issue 27004
Start page 1
End page 14
Total pages 14
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2017
Language eng
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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
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