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

• Published in: Scientific reports 2016-05, Vol.6 (1), p.27004-27004, Article 27004
• Main Authors: Wali, Gautam, Sutharsan, Ratneswary, Fan, Yongjun, Stewart, Romal, Tello Velasquez, Johana, Sue, Carolyn M, Crane, Denis I., Mackay-Sim, Alan
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/100; 14; 14/19; 14/56; 14/63; 631/378/1689/364; 631/378/87; Adult; Age of Onset; Cell Line; Epothilones - pharmacology; Gene Expression Regulation; Humanities and Social Sciences; Humans; Hydrogen Peroxide - pharmacology; Microtubules - drug effects; Microtubules - metabolism; Microtubules - ultrastructure; Movement - drug effects; Movement - physiology; multidisciplinary; Mutation; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Olfactory Receptor Neurons - drug effects; Olfactory Receptor Neurons - metabolism; Olfactory Receptor Neurons - pathology; Oxidative Stress; Peroxisomes - drug effects; Peroxisomes - metabolism; Peroxisomes - ultrastructure; Science; Science (multidisciplinary); Signal Transduction; Spastic Paraplegia, Hereditary - genetics; Spastic Paraplegia, Hereditary - metabolism; Spastic Paraplegia, Hereditary - pathology; Spastin - genetics; Spastin - metabolism; Time-Lapse Imaging; Tubulin Modulators - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep27004

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.