Oxidative Stress-Induced Axon Fragmentation Is a Consequence of Reduced Axonal Transport in Hereditary Spastic Paraplegia SPAST Patient Neurons
Hereditary spastic paraplegia (HSP) is a group of inherited disorders characterized by progressive spasticity and paralysis of the lower limbs. Autosomal dominant mutations in SPAST gene account for ∼40% of adult-onset patients. We have previously shown that SPAST patient cells have reduced organell...
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Frontiers Media S.A.
2020-05-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2020.00401/full |
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doaj-80b5c527c6884da192ed4da05652fedf2020-11-25T02:10:43ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2020-05-011410.3389/fnins.2020.00401512070Oxidative Stress-Induced Axon Fragmentation Is a Consequence of Reduced Axonal Transport in Hereditary Spastic Paraplegia SPAST Patient NeuronsGautam Wali0Gautam Wali1Erandhi Liyanage2Nicholas F. Blair3Nicholas F. Blair4Ratneswary Sutharsan5Ratneswary Sutharsan6Jin-Sung Park7Jin-Sung Park8Alan Mackay-Sim9Alan Mackay-Sim10Carolyn M. Sue11Carolyn M. Sue12Department of Neurogenetics, Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW, AustraliaSydney Medical School, The University of Sydney, Sydney, NSW, AustraliaDepartment of Neurogenetics, Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW, AustraliaDepartment of Neurogenetics, Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW, AustraliaSydney Medical School, The University of Sydney, Sydney, NSW, AustraliaGriffith Institute for Drug Discovery, Griffith University, Nathan, QLD, AustraliaQueensland Brain Institute, The University of Queensland, Brisbane, QLD, AustraliaDepartment of Neurogenetics, Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW, AustraliaDepartment of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, South KoreaSydney Medical School, The University of Sydney, Sydney, NSW, AustraliaGriffith Institute for Drug Discovery, Griffith University, Nathan, QLD, AustraliaDepartment of Neurogenetics, Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW, AustraliaSydney Medical School, The University of Sydney, Sydney, NSW, AustraliaHereditary spastic paraplegia (HSP) is a group of inherited disorders characterized by progressive spasticity and paralysis of the lower limbs. Autosomal dominant mutations in SPAST gene account for ∼40% of adult-onset patients. We have previously shown that SPAST patient cells have reduced organelle transport and are therefore more sensitive to oxidative stress. To test whether these effects are present in neuronal cells, we first generated 11 induced pluripotent stem (iPS) cell lines from fibroblasts of three healthy controls and three HSP patients with different SPAST mutations. These cells were differentiated into FOXG1-positive forebrain neurons and then evaluated for multiple aspects of axonal transport and fragmentation. Patient neurons exhibited reduced levels of SPAST encoded spastin, as well as a range of axonal deficits, including reduced levels of stabilized microtubules, lower peroxisome transport speed as a consequence of reduced microtubule-dependent transport, reduced number of peroxisomes, and higher density of axon swellings. Patient axons fragmented significantly more than controls following hydrogen peroxide exposure, suggesting for the first time that the SPAST patient axons are more sensitive than controls to the deleterious effects of oxidative stress. Treatment of patient neurons with tubulin-binding drugs epothilone D and noscapine rescued axon peroxisome transport and protected them against axon fragmentation induced by oxidative stress, showing that SPAST patient axons are vulnerable to oxidative stress-induced degeneration as a consequence of reduced axonal transport.https://www.frontiersin.org/article/10.3389/fnins.2020.00401/fullhereditary spastic paraplegiaSPASTaxon transportperoxisomesaxon degenerationepothilone D |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Gautam Wali Gautam Wali Erandhi Liyanage Nicholas F. Blair Nicholas F. Blair Ratneswary Sutharsan Ratneswary Sutharsan Jin-Sung Park Jin-Sung Park Alan Mackay-Sim Alan Mackay-Sim Carolyn M. Sue Carolyn M. Sue |
| spellingShingle |
Gautam Wali Gautam Wali Erandhi Liyanage Nicholas F. Blair Nicholas F. Blair Ratneswary Sutharsan Ratneswary Sutharsan Jin-Sung Park Jin-Sung Park Alan Mackay-Sim Alan Mackay-Sim Carolyn M. Sue Carolyn M. Sue Oxidative Stress-Induced Axon Fragmentation Is a Consequence of Reduced Axonal Transport in Hereditary Spastic Paraplegia SPAST Patient Neurons Frontiers in Neuroscience hereditary spastic paraplegia SPAST axon transport peroxisomes axon degeneration epothilone D |
| author_facet |
Gautam Wali Gautam Wali Erandhi Liyanage Nicholas F. Blair Nicholas F. Blair Ratneswary Sutharsan Ratneswary Sutharsan Jin-Sung Park Jin-Sung Park Alan Mackay-Sim Alan Mackay-Sim Carolyn M. Sue Carolyn M. Sue |
| author_sort |
Gautam Wali |
| title |
Oxidative Stress-Induced Axon Fragmentation Is a Consequence of Reduced Axonal Transport in Hereditary Spastic Paraplegia SPAST Patient Neurons |
| title_short |
Oxidative Stress-Induced Axon Fragmentation Is a Consequence of Reduced Axonal Transport in Hereditary Spastic Paraplegia SPAST Patient Neurons |
| title_full |
Oxidative Stress-Induced Axon Fragmentation Is a Consequence of Reduced Axonal Transport in Hereditary Spastic Paraplegia SPAST Patient Neurons |
| title_fullStr |
Oxidative Stress-Induced Axon Fragmentation Is a Consequence of Reduced Axonal Transport in Hereditary Spastic Paraplegia SPAST Patient Neurons |
| title_full_unstemmed |
Oxidative Stress-Induced Axon Fragmentation Is a Consequence of Reduced Axonal Transport in Hereditary Spastic Paraplegia SPAST Patient Neurons |
| title_sort |
oxidative stress-induced axon fragmentation is a consequence of reduced axonal transport in hereditary spastic paraplegia spast patient neurons |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Neuroscience |
| issn |
1662-453X |
| publishDate |
2020-05-01 |
| description |
Hereditary spastic paraplegia (HSP) is a group of inherited disorders characterized by progressive spasticity and paralysis of the lower limbs. Autosomal dominant mutations in SPAST gene account for ∼40% of adult-onset patients. We have previously shown that SPAST patient cells have reduced organelle transport and are therefore more sensitive to oxidative stress. To test whether these effects are present in neuronal cells, we first generated 11 induced pluripotent stem (iPS) cell lines from fibroblasts of three healthy controls and three HSP patients with different SPAST mutations. These cells were differentiated into FOXG1-positive forebrain neurons and then evaluated for multiple aspects of axonal transport and fragmentation. Patient neurons exhibited reduced levels of SPAST encoded spastin, as well as a range of axonal deficits, including reduced levels of stabilized microtubules, lower peroxisome transport speed as a consequence of reduced microtubule-dependent transport, reduced number of peroxisomes, and higher density of axon swellings. Patient axons fragmented significantly more than controls following hydrogen peroxide exposure, suggesting for the first time that the SPAST patient axons are more sensitive than controls to the deleterious effects of oxidative stress. Treatment of patient neurons with tubulin-binding drugs epothilone D and noscapine rescued axon peroxisome transport and protected them against axon fragmentation induced by oxidative stress, showing that SPAST patient axons are vulnerable to oxidative stress-induced degeneration as a consequence of reduced axonal transport. |
| topic |
hereditary spastic paraplegia SPAST axon transport peroxisomes axon degeneration epothilone D |
| url |
https://www.frontiersin.org/article/10.3389/fnins.2020.00401/full |
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