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dc.contributor.authorAbrahamsen, Greger
dc.contributor.authorFan, Yongjun
dc.contributor.authorMatigian, Nicholas
dc.contributor.authorWali, Gautam
dc.contributor.authorBellette, Bernadette
dc.contributor.authorSutharsan, Ratneswary
dc.contributor.authorRaju, Jyothy
dc.contributor.authorWood, Stephen A
dc.contributor.authorVeivers, David
dc.contributor.authorSue, Carolyn M
dc.contributor.authorMackay-Sim, Alan
dc.date.accessioned2018-01-11T04:18:12Z
dc.date.available2018-01-11T04:18:12Z
dc.date.issued2013
dc.date.modified2014-01-22T23:06:38Z
dc.identifier.issn1754-8403
dc.identifier.doi10.1242/dmm.010884
dc.identifier.urihttp://hdl.handle.net/10072/55945
dc.description.abstractHereditary 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.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherThe Company of Biologists
dc.publisher.placeUnited Kingdom
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom489
dc.relation.ispartofpageto502
dc.relation.ispartofissue2
dc.relation.ispartofjournalDisease Models & Mechanisms
dc.relation.ispartofvolume6
dc.rights.retentionY
dc.subject.fieldofresearchNeurosciences not elsewhere classified
dc.subject.fieldofresearchBiological Sciences
dc.subject.fieldofresearchMedical and Health Sciences
dc.subject.fieldofresearchcode110999
dc.subject.fieldofresearchcode06
dc.subject.fieldofresearchcode11
dc.titleA patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by-nc-sa/3.0
dc.description.versionVersion of Record (VoR)
gro.facultyGriffith Sciences, Griffith Institute for Drug Discovery
gro.rights.copyright© 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.
gro.date.issued2013
gro.hasfulltextFull Text
gro.griffith.authorMackay-Sim, Alan
gro.griffith.authorMatigian, Nicholas
gro.griffith.authorAbrahamsen, Greger
gro.griffith.authorBellette, Bernadette
gro.griffith.authorSutharsan, Ratneswary
gro.griffith.authorWood, Stephen A.
gro.griffith.authorFan, Yongjun
gro.griffith.authorRaju, Jyothy
gro.griffith.authorWali, Gautam


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