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Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia
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. In olfactory stem cell lines derived from pati...
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Published in: | Scientific reports 2016-05, Vol.6 (1), p.27004-27004, Article 27004 |
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description | 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. 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. |
doi_str_mv | 10.1038/srep27004 |
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SPAST
, which encodes spastin a microtubule severing protein. 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.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep27004</identifier><identifier>PMID: 27229699</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/1 ; 13/100 ; 14 ; 14/19 ; 14/56 ; 14/63 ; 631/378/1689/364 ; 631/378/87 ; Adult ; Age of Onset ; Cell Line ; Epothilones - pharmacology ; Gene Expression Regulation ; Humanities and Social Sciences ; Humans ; Hydrogen Peroxide - pharmacology ; Microtubules - drug effects ; Microtubules - metabolism ; Microtubules - ultrastructure ; Movement - drug effects ; Movement - physiology ; multidisciplinary ; Mutation ; Neural Stem Cells - drug effects ; Neural Stem Cells - metabolism ; Neural Stem Cells - pathology ; Olfactory Receptor Neurons - drug effects ; Olfactory Receptor Neurons - metabolism ; Olfactory Receptor Neurons - pathology ; Oxidative Stress ; Peroxisomes - drug effects ; Peroxisomes - metabolism ; Peroxisomes - ultrastructure ; Science ; Science (multidisciplinary) ; Signal Transduction ; Spastic Paraplegia, Hereditary - genetics ; Spastic Paraplegia, Hereditary - metabolism ; Spastic Paraplegia, Hereditary - pathology ; Spastin - genetics ; Spastin - metabolism ; Time-Lapse Imaging ; Tubulin Modulators - pharmacology</subject><ispartof>Scientific reports, 2016-05, Vol.6 (1), p.27004-27004, Article 27004</ispartof><rights>The Author(s) 2016</rights><rights>Copyright © 2016, Macmillan Publishers Limited 2016 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c410t-58f00d733a7588a0eb95be3534a4e3c1cfe777bea0a09fc288d9b4892f979d543</citedby><cites>FETCH-LOGICAL-c410t-58f00d733a7588a0eb95be3534a4e3c1cfe777bea0a09fc288d9b4892f979d543</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882512/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882512/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,36992,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27229699$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wali, Gautam</creatorcontrib><creatorcontrib>Sutharsan, Ratneswary</creatorcontrib><creatorcontrib>Fan, Yongjun</creatorcontrib><creatorcontrib>Stewart, Romal</creatorcontrib><creatorcontrib>Tello Velasquez, Johana</creatorcontrib><creatorcontrib>Sue, Carolyn M</creatorcontrib><creatorcontrib>Crane, Denis I.</creatorcontrib><creatorcontrib>Mackay-Sim, Alan</creatorcontrib><title>Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>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. 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.</description><subject>13</subject><subject>13/1</subject><subject>13/100</subject><subject>14</subject><subject>14/19</subject><subject>14/56</subject><subject>14/63</subject><subject>631/378/1689/364</subject><subject>631/378/87</subject><subject>Adult</subject><subject>Age of Onset</subject><subject>Cell Line</subject><subject>Epothilones - pharmacology</subject><subject>Gene Expression Regulation</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Hydrogen Peroxide - pharmacology</subject><subject>Microtubules - drug effects</subject><subject>Microtubules - metabolism</subject><subject>Microtubules - ultrastructure</subject><subject>Movement - drug effects</subject><subject>Movement - physiology</subject><subject>multidisciplinary</subject><subject>Mutation</subject><subject>Neural Stem Cells - drug effects</subject><subject>Neural Stem Cells - metabolism</subject><subject>Neural Stem Cells - pathology</subject><subject>Olfactory Receptor Neurons - drug effects</subject><subject>Olfactory Receptor Neurons - metabolism</subject><subject>Olfactory Receptor Neurons - pathology</subject><subject>Oxidative Stress</subject><subject>Peroxisomes - drug effects</subject><subject>Peroxisomes - metabolism</subject><subject>Peroxisomes - ultrastructure</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signal Transduction</subject><subject>Spastic Paraplegia, Hereditary - genetics</subject><subject>Spastic Paraplegia, Hereditary - metabolism</subject><subject>Spastic Paraplegia, Hereditary - pathology</subject><subject>Spastin - genetics</subject><subject>Spastin - metabolism</subject><subject>Time-Lapse Imaging</subject><subject>Tubulin Modulators - pharmacology</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNptkdFqFTEQhhdRbGl74QtILlVYm83umuRGKKW1QsXCqddhNjs5J3U3iUm2tk_TVzXl1EMFc5Mw8_HPn_mr6k1DPza0FccpYmCc0u5Ftc9o19esZezls_dedZTSDS2nZ7Jr5Otqj3HG5Ccp96uHb6g34GyaiTfEzgFsxJHMVkefl2GZsB4xoBvRZRIw-jub_IwkRzDG6p_WrQm4kZT6CNneIkk5YkrEOrK6Olld1_OSIRdJjdOUiIl-JqGQRS-R3zZvyAWWiTZDvCerAClbTa4gQphwbeGwemVgSnj0dB9UP87Prk8v6svvX76enlzWumtornthKB152wLvhQCKg-wHbPu2gw5b3WiDnPMBgQKVRjMhRjl0QjIjuRz7rj2oPm91wzLMOOpiL8KkQrRzMaY8WPVvx9mNWvtb1QnB-oYVgXdPAtH_WjBlNdv0-Gdw6JekGi5Zy3tGRUHfb9Gy41TiM7sxDVWPmapdpoV9-9zXjvybYAE-bIFUWm6NUd34Jbqyq_-o_QEj9bCN</recordid><startdate>20160527</startdate><enddate>20160527</enddate><creator>Wali, Gautam</creator><creator>Sutharsan, Ratneswary</creator><creator>Fan, Yongjun</creator><creator>Stewart, Romal</creator><creator>Tello Velasquez, Johana</creator><creator>Sue, Carolyn M</creator><creator>Crane, Denis I.</creator><creator>Mackay-Sim, Alan</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160527</creationdate><title>Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia</title><author>Wali, Gautam ; Sutharsan, Ratneswary ; Fan, Yongjun ; Stewart, Romal ; Tello Velasquez, Johana ; Sue, Carolyn M ; Crane, Denis I. ; Mackay-Sim, Alan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c410t-58f00d733a7588a0eb95be3534a4e3c1cfe777bea0a09fc288d9b4892f979d543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>13</topic><topic>13/1</topic><topic>13/100</topic><topic>14</topic><topic>14/19</topic><topic>14/56</topic><topic>14/63</topic><topic>631/378/1689/364</topic><topic>631/378/87</topic><topic>Adult</topic><topic>Age of Onset</topic><topic>Cell Line</topic><topic>Epothilones - pharmacology</topic><topic>Gene Expression Regulation</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Hydrogen Peroxide - pharmacology</topic><topic>Microtubules - drug effects</topic><topic>Microtubules - metabolism</topic><topic>Microtubules - ultrastructure</topic><topic>Movement - drug effects</topic><topic>Movement - physiology</topic><topic>multidisciplinary</topic><topic>Mutation</topic><topic>Neural Stem Cells - drug effects</topic><topic>Neural Stem Cells - metabolism</topic><topic>Neural Stem Cells - pathology</topic><topic>Olfactory Receptor Neurons - drug effects</topic><topic>Olfactory Receptor Neurons - metabolism</topic><topic>Olfactory Receptor Neurons - pathology</topic><topic>Oxidative Stress</topic><topic>Peroxisomes - drug effects</topic><topic>Peroxisomes - metabolism</topic><topic>Peroxisomes - ultrastructure</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Signal Transduction</topic><topic>Spastic Paraplegia, Hereditary - genetics</topic><topic>Spastic Paraplegia, Hereditary - metabolism</topic><topic>Spastic Paraplegia, Hereditary - pathology</topic><topic>Spastin - genetics</topic><topic>Spastin - metabolism</topic><topic>Time-Lapse Imaging</topic><topic>Tubulin Modulators - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wali, Gautam</creatorcontrib><creatorcontrib>Sutharsan, Ratneswary</creatorcontrib><creatorcontrib>Fan, Yongjun</creatorcontrib><creatorcontrib>Stewart, Romal</creatorcontrib><creatorcontrib>Tello Velasquez, Johana</creatorcontrib><creatorcontrib>Sue, Carolyn M</creatorcontrib><creatorcontrib>Crane, Denis I.</creatorcontrib><creatorcontrib>Mackay-Sim, Alan</creatorcontrib><collection>Springer Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wali, Gautam</au><au>Sutharsan, Ratneswary</au><au>Fan, Yongjun</au><au>Stewart, Romal</au><au>Tello Velasquez, Johana</au><au>Sue, Carolyn M</au><au>Crane, Denis I.</au><au>Mackay-Sim, Alan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2016-05-27</date><risdate>2016</risdate><volume>6</volume><issue>1</issue><spage>27004</spage><epage>27004</epage><pages>27004-27004</pages><artnum>27004</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><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. 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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27229699</pmid><doi>10.1038/srep27004</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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source | Publicly Available Content (ProQuest); PubMed Central; Free Full-Text Journals in Chemistry; Springer Nature - nature.com Journals - Fully Open Access |
subjects | 13 13/1 13/100 14 14/19 14/56 14/63 631/378/1689/364 631/378/87 Adult Age of Onset Cell Line Epothilones - pharmacology Gene Expression Regulation Humanities and Social Sciences Humans Hydrogen Peroxide - pharmacology Microtubules - drug effects Microtubules - metabolism Microtubules - ultrastructure Movement - drug effects Movement - physiology multidisciplinary Mutation Neural Stem Cells - drug effects Neural Stem Cells - metabolism Neural Stem Cells - pathology Olfactory Receptor Neurons - drug effects Olfactory Receptor Neurons - metabolism Olfactory Receptor Neurons - pathology Oxidative Stress Peroxisomes - drug effects Peroxisomes - metabolism Peroxisomes - ultrastructure Science Science (multidisciplinary) Signal Transduction Spastic Paraplegia, Hereditary - genetics Spastic Paraplegia, Hereditary - metabolism Spastic Paraplegia, Hereditary - pathology Spastin - genetics Spastin - metabolism Time-Lapse Imaging Tubulin Modulators - pharmacology |
title | Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia |
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