SPAST (SPG4) HSP mechanism explained

Potential drug treatment identified


Yongjun Fan, Alan Mackay-Sim, Gautam Wali
Research team (L to R) Dr. Yongjun Fan, Prof. Alan Mackay-Sim, Dr. Gautam Wali


This paper by the Australian HSP research team provides a detailed explanation of the mechanics of just how SPAST (SPG4) mutations cause HSP. It also reveals how the drug epothilone D restores cell function to normal, thus identifying it as a potential treatment for this form of HSP.



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.

tracking peroxisome movement
tracking peroxisome movement


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.


Here is a link to the full text.


SOURCE: Sci Rep. 2016 May 27;6:27004. doi: 10.1038/srep27004 PMID: 27229699 [PubMed – in process]


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


Wali G1, Sutharsan R1, Fan Y1, Stewart R2, Tello Velasquez J1, Sue CM3, Crane DI1, Mackay-Sim A1.


1 Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Australia.

2 The University of Queensland Centre for Clinical Research, Brisbane, Australia.

3 Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.


  1. When would we be able to try this drug you found for Spg4 that could possibly be helpful? I am excited!!

    1. Editor’s Note: The next step is the clinical trials process, so in the best case scenario time and success wise, a treatment may be available in 2–3 years time… best case scenario!

  2. My daughter has been recently diagnosed with SPG4. She is 7years old. She doesn’t walk on her own, only with a walker or she crawls. I’m not sure how it could work being from the US, but I would love for her to be part of the clinical trial.

  3. Hello, I would like to know how far the experimentation of epothilone for patients with spg4 has progressed? Thanks

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