The ALS-Associated FUS (P525L) Variant Does Not Directly Interfere with Microtubule-Dependent Kinesin-1 Motility
Deficient intracellular transport is a common pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mutations in the fused-in-sarcoma (FUS) gene are one of the most common genetic causes for familial ALS. Motor neurons carrying a mutation in the nuc...
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MDPI AG
2021-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/5/2422 |
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| author | Anne Seifert Hauke Drechsler Julia Japtok Till Korten Stefan Diez Andreas Hermann |
| author_facet | Anne Seifert Hauke Drechsler Julia Japtok Till Korten Stefan Diez Andreas Hermann |
| author_sort | Anne Seifert |
| collection | DOAJ |
| description | Deficient intracellular transport is a common pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mutations in the fused-in-sarcoma (FUS) gene are one of the most common genetic causes for familial ALS. Motor neurons carrying a mutation in the nuclear localization sequence of FUS (P525L) show impaired axonal transport of several organelles, suggesting that mislocalized cytoplasmic FUS might directly interfere with the transport machinery. To test this hypothesis, we studied the effect of FUS on kinesin-1 motility in vitro. Using a modified microtubule gliding motility assay on surfaces coated with kinesin-1 motor proteins, we showed that neither recombinant wildtype and P525L FUS variants nor lysates from isogenic ALS-patient-specific iPSC-derived spinal motor neurons expressing those FUS variants significantly affected gliding velocities. We hence conclude that during ALS pathogenesis the initial negative effect of FUS (P525L) on axonal transport is an indirect nature and requires additional factors or mechanisms. |
| first_indexed | 2024-03-09T06:13:20Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T06:13:20Z |
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| spelling | doaj.art-1043b704a51b4916a77e3f33aa13e14d2023-12-03T11:55:25ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01225242210.3390/ijms22052422The ALS-Associated FUS (P525L) Variant Does Not Directly Interfere with Microtubule-Dependent Kinesin-1 MotilityAnne Seifert0Hauke Drechsler1Julia Japtok2Till Korten3Stefan Diez4Andreas Hermann5Department of Neurology, Technische Universität Dresden, 01307 Dresden, GermanyB CUBE—Center for Molecular Bioengineering and Cluster of Excellence Physics of Life, Technische Universität Dresden, 01307 Dresden, GermanyDepartment of Neurology, Technische Universität Dresden, 01307 Dresden, GermanyB CUBE—Center for Molecular Bioengineering and Cluster of Excellence Physics of Life, Technische Universität Dresden, 01307 Dresden, GermanyB CUBE—Center for Molecular Bioengineering and Cluster of Excellence Physics of Life, Technische Universität Dresden, 01307 Dresden, GermanyDepartment of Neurology, Technische Universität Dresden, 01307 Dresden, GermanyDeficient intracellular transport is a common pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mutations in the fused-in-sarcoma (FUS) gene are one of the most common genetic causes for familial ALS. Motor neurons carrying a mutation in the nuclear localization sequence of FUS (P525L) show impaired axonal transport of several organelles, suggesting that mislocalized cytoplasmic FUS might directly interfere with the transport machinery. To test this hypothesis, we studied the effect of FUS on kinesin-1 motility in vitro. Using a modified microtubule gliding motility assay on surfaces coated with kinesin-1 motor proteins, we showed that neither recombinant wildtype and P525L FUS variants nor lysates from isogenic ALS-patient-specific iPSC-derived spinal motor neurons expressing those FUS variants significantly affected gliding velocities. We hence conclude that during ALS pathogenesis the initial negative effect of FUS (P525L) on axonal transport is an indirect nature and requires additional factors or mechanisms.https://www.mdpi.com/1422-0067/22/5/2422motor neuronsaxonopathymolecular motorsaxonal transportgliding motility assays |
| spellingShingle | Anne Seifert Hauke Drechsler Julia Japtok Till Korten Stefan Diez Andreas Hermann The ALS-Associated FUS (P525L) Variant Does Not Directly Interfere with Microtubule-Dependent Kinesin-1 Motility International Journal of Molecular Sciences motor neurons axonopathy molecular motors axonal transport gliding motility assays |
| title | The ALS-Associated FUS (P525L) Variant Does Not Directly Interfere with Microtubule-Dependent Kinesin-1 Motility |
| title_full | The ALS-Associated FUS (P525L) Variant Does Not Directly Interfere with Microtubule-Dependent Kinesin-1 Motility |
| title_fullStr | The ALS-Associated FUS (P525L) Variant Does Not Directly Interfere with Microtubule-Dependent Kinesin-1 Motility |
| title_full_unstemmed | The ALS-Associated FUS (P525L) Variant Does Not Directly Interfere with Microtubule-Dependent Kinesin-1 Motility |
| title_short | The ALS-Associated FUS (P525L) Variant Does Not Directly Interfere with Microtubule-Dependent Kinesin-1 Motility |
| title_sort | als associated fus p525l variant does not directly interfere with microtubule dependent kinesin 1 motility |
| topic | motor neurons axonopathy molecular motors axonal transport gliding motility assays |
| url | https://www.mdpi.com/1422-0067/22/5/2422 |
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