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Adult-onset HSP is most commonly caused by mutations in <jats:italic>SPAST<\/jats:italic>, which encodes spastin a microtubule severing protein. In olfactory stem cell lines derived from patients carrying different <jats:italic>SPAST<\/jats:italic> 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 <jats:italic>SPAST<\/jats:italic> mutations indirectly lead to impaired peroxisome transport and oxidative stress.<\/jats:p>","DOI":"10.1038\/srep27004","type":"journal-article","created":{"date-parts":[[2016,5,27]],"date-time":"2016-05-27T09:15:20Z","timestamp":1464340520000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia"],"prefix":"10.1038","volume":"6","author":[{"given":"Gautam","family":"Wali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratneswary","family":"Sutharsan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjun","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romal","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johana","family":"Tello Velasquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn M","family":"Sue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis I.","family":"Crane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Mackay-Sim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,5,27]]},"reference":[{"key":"BFsrep27004_CR1","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1016\/S1474-4422(08)70258-8","volume":"7","author":"S Salinas","year":"2008","unstructured":"Salinas, S., Proukakis, C., Crosby, A. & Warner, T. 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