title: Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia.
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.
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Australia.
authors.forename: Gautam
authors.initials: G
authors.lastname: Wali
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Australia.
authors.forename: Ratneswary
authors.initials: R
authors.lastname: Sutharsan
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Australia.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Fan
authors.affiliation: The University of Queensland Centre for Clinical Research, Brisbane, Australia.
authors.forename: Romal
authors.initials: R
authors.lastname: Stewart
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Australia.
authors.forename: Johana
authors.initials: J
authors.lastname: Tello Velasquez
authors.affiliation: Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Sue
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Australia.
authors.forename: Denis I
authors.initials: DI
authors.lastname: Crane
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Australia.
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay-Sim
mesh_terms: D000328:Adult; D017668:Age of Onset; D002460:Cell Line; D034261:Epothilones / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009068:Movement / Q000187:drug effects / Q000502:physiology; D009154:Mutation; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018034:Olfactory Receptor Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D020675:Peroxisomes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D015398:Signal Transduction; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000074181:Spastin / Q000235:genetics* / Q000378:metabolism; D059008:Time-Lapse Imaging; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D034261:Epothilones; D050257:Tubulin Modulators; D006861:Hydrogen Peroxide; D000074181:Spastin; C400283:SPAST protein, human