التفاصيل البيبلوغرافية
| العنوان: |
Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia |
| المؤلفون: |
Yongjun Fan, Gautam Wali, Alan Mackay-Sim, Romal Stewart, Johana Tello Velasquez, Denis I. Crane, Ratneswary Sutharsan, Carolyn M. Sue |
| المصدر: |
Scientific Reports |
| بيانات النشر: |
Nature Publishing Group, 2016. |
| سنة النشر: |
2016 |
| مصطلحات موضوعية: |
0301 basic medicine, Adult, Spastin, Hereditary spastic paraplegia, Movement, Biology, medicine.disease_cause, Microtubules, Time-Lapse Imaging, Olfactory Receptor Neurons, Article, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, medicine, Peroxisomes, Humans, Age of Onset, Microtubule severing, Mutation, Multidisciplinary, Spastic Paraplegia, Hereditary, Neurodegeneration, Hydrogen Peroxide, Peroxisome, medicine.disease, Tubulin Modulators, 3. Good health, Cell biology, Oxidative Stress, 030104 developmental biology, Biochemistry, Gene Expression Regulation, Catalase, Epothilones, biology.protein, 030217 neurology & neurosurgery, Oxidative stress, Signal Transduction |
| الوصف: |
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. |
| اللغة: |
English |
| تدمد: |
2045-2322 |
| DOI: |
10.1038/srep27004 |
| URL الوصول: |
https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0aeefbaf51335af7a2a4d5fd0400cd91 |
| Rights: |
OPEN |
| رقم الانضمام: |
edsair.doi.dedup.....0aeefbaf51335af7a2a4d5fd0400cd91 |
| قاعدة البيانات: |
OpenAIRE |