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  • Low dose tubulin-binding drugs rescue peroxisome trafficking deficit in patient-derived stem cells in Hereditary Spastic Paraplegia

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    Author(s)
    Fan, Yongjun
    Wali, Gautam
    Sutharsan, Ratneswary
    Bellette, Bernadette
    Crane, Denis I
    Sue, Carolyn M
    Mackay-Sim, Alan
    Griffith University Author(s)
    Crane, Denis I.
    Mackay-Sim, Alan
    Bellette, Bernadette
    Sutharsan, Ratneswary
    Fan, Yongjun
    Wali, Gautam
    Year published
    2014
    Metadata
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    Abstract
    Hereditary Spastic Paraplegia (HSP) is a genetically heterogeneous group of disorders, diagnosed by progressive gait disturbances with muscle weakness and spasticity, for which there are no treatments targeted at the underlying pathophysiology. Mutations in spastin are a common cause of HSP. Spastin is a microtubule-severing protein whose mutation in mouse causes defective axonal transport. In human patient-derived olfactory neurosphere-derived (ONS) cells, spastin mutations lead to lower levels of acetylated a-tubulin, a marker of stabilised microtubules, and to slower speed of peroxisome trafficking. Here we screened ...
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    Hereditary Spastic Paraplegia (HSP) is a genetically heterogeneous group of disorders, diagnosed by progressive gait disturbances with muscle weakness and spasticity, for which there are no treatments targeted at the underlying pathophysiology. Mutations in spastin are a common cause of HSP. Spastin is a microtubule-severing protein whose mutation in mouse causes defective axonal transport. In human patient-derived olfactory neurosphere-derived (ONS) cells, spastin mutations lead to lower levels of acetylated a-tubulin, a marker of stabilised microtubules, and to slower speed of peroxisome trafficking. Here we screened multiple concentrations of four tubulin-binding drugs for their ability to rescue levels of acetylated a-tubulin in patient-derived ONS cells. Drug doses that restored acetylated a-tubulin to levels in control-derived ONS cells were then selected for their ability to rescue peroxisome trafficking deficits. Automated microscopic screening identified very low doses of the four drugs (0.5 nM taxol, 0.5 nM vinblastine, 2 nM epothilone D, 10 占noscapine) that rescued acetylated a-tubulin in patient-derived ONS cells. These same doses rescued peroxisome trafficking deficits, restoring peroxisome speeds to untreated control cell levels. These results demonstrate a novel approach for drug screening based on high throughput automated microscopy for acetylated a-tubulin followed by functional validation of microtubule-based peroxisome transport. From a clinical perspective, all the drugs tested are used clinically, but at much higher doses. Importantly, epothilone D and noscapine can enter the central nervous system, making them potential candidates for future clinical trials.
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    Journal Title
    Biology Open
    Volume
    3
    DOI
    https://doi.org/10.1242/bio.20147641
    Copyright Statement
    © The Author(s) 2014. This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
    Subject
    Biochemistry and Cell Biology not elsewhere classified
    Neurology and Neuromuscular Diseases
    Other Biological Sciences
    Publication URI
    http://hdl.handle.net/10072/65232
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    • Journal articles

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