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  • A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations

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    Author(s)
    Abrahamsen, Greger
    Fan, Yongjun
    Matigian, Nicholas
    Wali, Gautam
    Bellette, Bernadette
    Sutharsan, Ratneswary
    Raju, Jyothy
    Wood, Stephen A
    Veivers, David
    Sue, Carolyn M
    Mackay-Sim, Alan
    Griffith University Author(s)
    Mackay-Sim, Alan
    Matigian, Nicholas
    Abrahamsen, Greger
    Bellette, Bernadette
    Sutharsan, Ratneswary
    Wood, Stephen A.
    Fan, Yongjun
    Raju, Jyothy
    Wali, Gautam
    Year published
    2013
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    Abstract
    Hereditary spastic paraplegia (HSP) leads to progressive gait disturbances with lower limb muscle weakness and spasticity. Mutations in SPAST are a major cause of adult-onset, autosomal-dominant HSP. Spastin, the protein encoded by SPAST, is a microtubule-severing protein that is enriched in the distal axon of corticospinal motor neurons, which degenerate in HSP patients. Animal and cell models have identified functions of spastin and mutated spastin but these models lack the gene dosage, mutation variability and genetic background that characterize patients with the disease. In this study, this genetic variability is ...
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    Hereditary spastic paraplegia (HSP) leads to progressive gait disturbances with lower limb muscle weakness and spasticity. Mutations in SPAST are a major cause of adult-onset, autosomal-dominant HSP. Spastin, the protein encoded by SPAST, is a microtubule-severing protein that is enriched in the distal axon of corticospinal motor neurons, which degenerate in HSP patients. Animal and cell models have identified functions of spastin and mutated spastin but these models lack the gene dosage, mutation variability and genetic background that characterize patients with the disease. In this study, this genetic variability is encompassed by comparing neural progenitor cells derived from biopsies of the olfactory mucosa from healthy controls with similar cells from HSP patients with SPAST mutations, in order to identify cell functions altered in HSP. Patient-derived cells were similar to control-derived cells in proliferation and multiple metabolic functions but had major dysregulation of gene expression, with 57% of all mRNA transcripts affected, including many associated with microtubule dynamics. Compared to control cells, patient-derived cells had 50% spastin, 50% acetylated a-tubulin and 150% stathmin, a microtubule-destabilizing enzyme. Patient-derived cells were smaller than control cells. They had altered intracellular distributions of peroxisomes and mitochondria and they had slower moving peroxisomes. These results suggest that patient-derived cells might compensate for reduced spastin, but their increased stathmin expression reduced stabilized microtubules and altered organelle trafficking. Sub-nanomolar concentrations of the microtubule-binding drugs, paclitaxel and vinblastine, increased acetylated a-tubulin levels in patient cells to control levels, indicating the utility of this cell model for screening other candidate compounds for drug therapies.
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    Journal Title
    Disease Models & Mechanisms
    Volume
    6
    Issue
    2
    DOI
    https://doi.org/10.1242/dmm.010884
    Copyright Statement
    © 2013. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.
    Subject
    Neurosciences not elsewhere classified
    Biological Sciences
    Medical and Health Sciences
    Publication URI
    http://hdl.handle.net/10072/55945
    Collection
    • Journal articles

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