Posted - May 2020 in Research Highlights
Consequence of higher sensitivity to oxidative stress
Oxidative stress has been shown in this lab study to cause damage to the axons of neurons with SPAST mutations.
The HSP neurons are more sensitive than unaffected neurons to the damaging effects of oxidative stress.
The oxidative stress damage was shown to be a consequence of reduced transport in the axons.
This important study is the work of members of the research team and part of the HSP Research Program supported by this Foundation.
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.
SOURCE: Front. Neurosci., 07 May 2020 https://doi.org/10.3389/fnins.2020.00401
Oxidative Stress-Induced Axon Fragmentation Is a Consequence of Reduced Axonal Transport in Hereditary Spastic Paraplegia SPAST Patient Neurons
Gautam Wali1,2*, Erandhi Liyanage1, Nicholas F. Blair1,2, Ratneswary Sutharsan3,4, Jin-Sung Park1,5, Alan Mackay-Sim2,3† and Carolyn M. Sue1,2*†
1 Department of Neurogenetics, Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia
2 Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
3 Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia
4 Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
5 Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea