SPAST (SPG4) HSP mechanism explained

Posted - June 2016 in Research Highlights

Potential drug treatment identified

 

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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.

 

Abstract

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.

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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.