{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:29:56Z","timestamp":1791350996089,"version":"4.3.1"},"reference-count":46,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":3059,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>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 \u03b1-tubulin and 150% stathmin, a microtubule-destabilising 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 stabilised microtubules and altered organelle trafficking. Sub-nanomolar concentrations of the microtubule-binding drugs, paclitaxel and vinblastine, increased acetylated \u03b1-tubulin levels in patient cells to control levels, indicating the utility of this cell model for screening other candidate compounds for drug therapies.<\/jats:p>","DOI":"10.1242\/dmm.010884","type":"journal-article","created":{"date-parts":[[2012,12,23]],"date-time":"2012-12-23T01:23:59Z","timestamp":1356225839000},"source":"Crossref","is-referenced-by-count":39,"title":["A patient-derived stem cell model of hereditary spastic paraplegia with <i>SPAST<\/i> mutations"],"prefix":"10.1242","author":[{"given":"Greger","family":"Abrahamsen","sequence":"first","affiliation":[{"name":"Griffith University, Brisbane, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjun","family":"Fan","sequence":"additional","affiliation":[{"name":"Griffith University, Brisbane, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Matigian","sequence":"additional","affiliation":[{"name":"Griffith University, Brisbane, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gautam","family":"Wali","sequence":"additional","affiliation":[{"name":"Griffith University, Brisbane, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernadette","family":"Bellette","sequence":"additional","affiliation":[{"name":"Griffith University, Brisbane, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratneswary","family":"Sutharsan","sequence":"additional","affiliation":[{"name":"Griffith University, Brisbane, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyothy","family":"Raju","sequence":"additional","affiliation":[{"name":"Griffith University, Brisbane, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"Wood","sequence":"additional","affiliation":[{"name":"Griffith University, Brisbane, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Veivers","sequence":"additional","affiliation":[{"name":"University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn M.","family":"Sue","sequence":"additional","affiliation":[{"name":"University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Mackay-Sim","sequence":"additional","affiliation":[{"name":"Griffith University, Brisbane, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2013,1,1]]},"reference":[{"key":"2021042513084372700_b1-0060489","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nrn2946","article-title":"Hereditary spastic paraplegias: membrane traffic and the motor pathway","volume":"12","author":"Blackstone","year":"2011","journal-title":"Nat. Rev. Neurosci."},{"key":"2021042513084372700_b2-0060489","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1083\/jcb.119.4.867","article-title":"Newly assembled microtubules are concentrated in the proximal and distal regions of growing axons","volume":"119","author":"Brown","year":"1992","journal-title":"J. Cell Biol."},{"key":"2021042513084372700_b3-0060489","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/S0955-0674(01)00289-7","article-title":"The oncoprotein 18\/stathmin family of microtubule destabilizers","volume":"14","author":"Cassimeris","year":"2002","journal-title":"Curr. Opin. Cell Biol."},{"key":"2021042513084372700_b4-0060489","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1093\/hmg\/ddg004","article-title":"Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus","volume":"12","author":"Charvin","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"2021042513084372700_b5-0060489","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.yexcr.2005.06.009","article-title":"Spastin subcellular localization is regulated through usage of different translation start sites and active export from the nucleus","volume":"309","author":"Claudiani","year":"2005","journal-title":"Exp. Cell Res."},{"key":"2021042513084372700_b6-0060489","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/nrn2631","article-title":"Microtubule assembly, organization and dynamics in axons and dendrites","volume":"10","author":"Conde","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"2021042513084372700_b7-0060489","doi-asserted-by":"crossref","first-page":"e21907","DOI":"10.1371\/journal.pone.0021907","article-title":"NRF2 activation restores disease related metabolic deficiencies in olfactory neurosphere-derived cells from patients with sporadic Parkinson's disease","volume":"6","author":"Cook","year":"2011","journal-title":"PLoS ONE"},{"key":"2021042513084372700_b8-0060489","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.abb.2011.02.012","article-title":"Kinesins and protein kinases: key players in the regulation of microtubule dynamics and organization","volume":"510","author":"Daire","year":"2011","journal-title":"Arch. Biochem. Biophys."},{"key":"2021042513084372700_b9-0060489","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1111\/j.1365-2990.2004.00587.x","article-title":"The extent of axonal loss in the long tracts in hereditary spastic paraplegia","volume":"30","author":"Deluca","year":"2004","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"2021042513084372700_b10-0060489","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1093\/bioinformatics\/btn224","article-title":"lumi: a pipeline for processing Illumina microarray","volume":"24","author":"Du","year":"2008","journal-title":"Bioinformatics"},{"key":"2021042513084372700_b11-0060489","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1093\/hmg\/11.2.153","article-title":"Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics","volume":"11","author":"Errico","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"2021042513084372700_b12-0060489","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.biopsych.2011.10.004","article-title":"Altered cell cycle dynamics in schizophrenia","volume":"71","author":"Fan","year":"2012","journal-title":"Biol. Psychiatry"},{"key":"2021042513084372700_b13-0060489","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1001\/archotol.124.8.861","article-title":"New techniques for biopsy and culture of human olfactory epithelial neurons","volume":"124","author":"F\u00e9ron","year":"1998","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"2021042513084372700_b14-0060489","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/(SICI)1097-0215(19980105)75:1<57::AID-IJC10>3.0.CO;2-A","article-title":"Combinations of paclitaxel and vinblastine and their effects on tubulin polymerization and cellular cytotoxicity: characterization of a synergistic schedule","volume":"75","author":"Giannakakou","year":"1998","journal-title":"Int. J. Cancer"},{"key":"2021042513084372700_b15-0060489","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1007\/s00234-005-1415-3","article-title":"Spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia","volume":"47","author":"Hedera","year":"2005","journal-title":"Neuroradiology"},{"key":"2021042513084372700_b16-0060489","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1152\/physrev.00023.2007","article-title":"Intracellular transport and kinesin superfamily proteins, KIFs: structure, function, and dynamics","volume":"88","author":"Hirokawa","year":"2008","journal-title":"Physiol. Rev."},{"key":"2021042513084372700_b17-0060489","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/417455a","article-title":"HDAC6 is a microtubule-associated deacetylase","volume":"417","author":"Hubbert","year":"2002","journal-title":"Nature"},{"key":"2021042513084372700_b18-0060489","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/j.1471-4159.2009.06104.x","article-title":"Direct evidence for axonal transport defects in a novel mouse model of mutant spastin-induced hereditary spastic paraplegia (HSP) and human HSP patients","volume":"110","author":"Kasher","year":"2009","journal-title":"J. Neurochem."},{"key":"2021042513084372700_b19-0060489","doi-asserted-by":"crossref","first-page":"2597","DOI":"10.1002\/j.1460-2075.1987.tb02550.x","article-title":"Microtubules containing detyrosinated tubulin are less dynamic","volume":"6","author":"Kreis","year":"1987","journal-title":"EMBO J."},{"key":"2021042513084372700_b20-0060489","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1002\/stem.1220","article-title":"Concise review: patient-derived olfactory stem cells: new models for brain diseases","volume":"30","author":"Mackay-Sim","year":"2012","journal-title":"Stem Cells"},{"key":"2021042513084372700_b21-0060489","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1074\/jbc.M510661200","article-title":"Stathmin strongly increases the minus end catastrophe frequency and induces rapid treadmilling of bovine brain microtubules at steady state in vitro","volume":"281","author":"Manna","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021042513084372700_b22-0060489","doi-asserted-by":"crossref","first-page":"15640","DOI":"10.1074\/jbc.M900343200","article-title":"Regulation of microtubule dynamic instability in vitro by differentially phosphorylated stathmin","volume":"284","author":"Manna","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2021042513084372700_b23-0060489","doi-asserted-by":"crossref","first-page":"e1002207","DOI":"10.1371\/journal.pgen.1002207","article-title":"Variance of gene expression identifies altered network constraints in neurological disease","volume":"7","author":"Mar","year":"2011","journal-title":"PLoS Genet."},{"key":"2021042513084372700_b24-0060489","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1242\/dmm.005447","article-title":"Disease-specific, neurosphere-derived cells as models for brain disorders","volume":"3","author":"Matigian","year":"2010","journal-title":"Dis. Model. Mech."},{"key":"2021042513084372700_b25-0060489","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1002\/ana.10757","article-title":"Hereditary spastic paraparesis: disrupted intracellular transport associated with spastin mutation","volume":"54","author":"McDermott","year":"2003","journal-title":"Ann. Neurol."},{"key":"2021042513084372700_b26-0060489","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1212\/01.WNL.0000118204.90814.5A","article-title":"Large-scale disruption of microtubule pathways in morphologically normal human spastin muscle","volume":"62","author":"Molon","year":"2004","journal-title":"Neurology"},{"key":"2021042513084372700_b27-0060489","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1002\/dvdy.20360","article-title":"Multipotent stem cells from adult olfactory mucosa","volume":"233","author":"Murrell","year":"2005","journal-title":"Dev. Dyn."},{"key":"2021042513084372700_b28-0060489","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1242\/jcs.02776","article-title":"Failure of microtubule-mediated peroxisome division and trafficking in disorders with reduced peroxisome abundance","volume":"119","author":"Nguyen","year":"2006","journal-title":"J. Cell Sci."},{"key":"2021042513084372700_b29-0060489","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.neures.2007.06.1464","article-title":"Motor discoordination of transgenic mice overexpressing a microtubule destabilizer, stathmin, specifically in Purkinje cells","volume":"59","author":"Ohkawa","year":"2007","journal-title":"Neurosci. Res."},{"key":"2021042513084372700_b30-0060489","doi-asserted-by":"crossref","first-page":"3026","DOI":"10.1172\/JCI24694","article-title":"Disease-related phenotypes in a Drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine","volume":"115","author":"Orso","year":"2005","journal-title":"J. Clin. Invest."},{"key":"2021042513084372700_b31-0060489","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1172\/JCI40979","article-title":"Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network","volume":"120","author":"Park","year":"2010","journal-title":"J. Clin. Invest."},{"key":"2021042513084372700_b32-0060489","doi-asserted-by":"crossref","first-page":"e36","DOI":"10.1093\/nar\/30.9.e36","article-title":"Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR","volume":"30","author":"Pfaffl","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"2021042513084372700_b33-0060489","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1083\/jcb.104.2.289","article-title":"Microtubules containing acetylated alpha-tubulin in mammalian cells in culture","volume":"104","author":"Piperno","year":"1987","journal-title":"J. Cell Biol."},{"key":"2021042513084372700_b34-0060489","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1111\/j.1471-4159.2009.05875.x","article-title":"Pleiotropic effects of spastin on neurite growth depending on expression levels","volume":"108","author":"Riano","year":"2009","journal-title":"J. Neurochem."},{"key":"2021042513084372700_b35-0060489","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.ceb.2009.11.001","article-title":"Microtubule-severing enzymes","volume":"22","author":"Roll-Mecak","year":"2010","journal-title":"Curr. Opin. Cell Biol."},{"key":"2021042513084372700_b36-0060489","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1002\/jnr.21238","article-title":"Spastin and microtubules: Functions in health and disease","volume":"85","author":"Salinas","year":"2007","journal-title":"J. Neurosci. Res."},{"key":"2021042513084372700_b37-0060489","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/S1474-4422(08)70258-8","article-title":"Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms","volume":"7","author":"Salinas","year":"2008","journal-title":"Lancet Neurol."},{"key":"2021042513084372700_b38-0060489","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1093\/hmg\/ddi447","article-title":"Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners","volume":"15","author":"Sanderson","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"2021042513084372700_b39-0060489","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1093\/bioinformatics\/bti304","article-title":"ExPrimer: to design primers from exon-exon junctions","volume":"21","author":"Sandhu","year":"2005","journal-title":"Bioinformatics"},{"key":"2021042513084372700_b40-0060489","doi-asserted-by":"crossref","first-page":"2767","DOI":"10.1093\/hmg\/ddq177","article-title":"Evaluation of loss of function as an explanation for SPG4-based hereditary spastic paraplegia","volume":"19","author":"Solowska","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"2021042513084372700_b41-0060489","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1016\/S0002-9440(10)63426-8","article-title":"Dysregulation of stathmin, a microtubule-destabilizing protein, and up-regulation of Hsp25, Hsp27, and the antioxidant peroxiredoxin 6 in a mouse model of familial amyotrophic lateral sclerosis","volume":"165","author":"Strey","year":"2004","journal-title":"Am. J. Pathol."},{"key":"2021042513084372700_b42-0060489","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1016\/j.cub.2004.06.058","article-title":"The hereditary spastic paraplegia gene, spastin, regulates microtubule stability to modulate synaptic structure and function","volume":"14","author":"Trotta","year":"2004","journal-title":"Curr. Biol."},{"key":"2021042513084372700_b43-0060489","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1111\/j.1445-5994.2012.02941.x","article-title":"SPAST mutations in Australian patients with hereditary spastic paraplegia","volume":"42","author":"Vandebona","year":"2012","journal-title":"Int. Med. J."},{"key":"2021042513084372700_b44-0060489","doi-asserted-by":"crossref","first-page":"9040","DOI":"10.1073\/pnas.84.24.9040","article-title":"Differential turnover of tyrosinated and detyrosinated microtubules","volume":"84","author":"Webster","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042513084372700_b45-0060489","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1093\/hmg\/ddq058","article-title":"Stathmin, a microtubule-destabilizing protein, is dysregulated in spinal muscular atrophy","volume":"19","author":"Wen","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"2021042513084372700_b46-0060489","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1091\/mbc.e07-09-0878","article-title":"The microtubule-severing proteins spastin and katanin participate differently in the formation of axonal branches","volume":"19","author":"Yu","year":"2008","journal-title":"Mol. Biol. Cell"}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/6\/2\/489\/1864247\/489.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.010884\/2035578\/dmm_010884.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.010884\/2035578\/dmm_010884.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T20:32:27Z","timestamp":1621369947000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/doi\/10.1242\/dmm.010884\/258845\/A-patient-derived-stem-cell-model-of-hereditary"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,1,1]]},"references-count":46,"URL":"https:\/\/doi.org\/10.1242\/dmm.010884","relation":{},"ISSN":["1754-8411","1754-8403"],"issn-type":[{"value":"1754-8411","type":"electronic"},{"value":"1754-8403","type":"print"}],"subject":[],"published":{"date-parts":[[2013,1,1]]},"article-number":"dmm.010884"}}