Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons
Mutations in SPG11 cause a complicated autosomal recessive form of hereditary spastic paraplegia (HSP). Mechanistically, there are indications for the dysregulation of the GSK3β/βCat signaling pathway in SPG11. In this study, we tested the therapeutic potential of the GSK3β inhibitor, tideglusib, to...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-12-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2018.00914/full |
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| author | Tatyana Pozner Annika Schray Martin Regensburger Martin Regensburger Martin Regensburger Dieter Chichung Lie Ursula Schlötzer-Schrehardt Jürgen Winkler Jürgen Winkler Soeren Turan Soeren Turan Beate Winner Beate Winner |
| author_facet | Tatyana Pozner Annika Schray Martin Regensburger Martin Regensburger Martin Regensburger Dieter Chichung Lie Ursula Schlötzer-Schrehardt Jürgen Winkler Jürgen Winkler Soeren Turan Soeren Turan Beate Winner Beate Winner |
| author_sort | Tatyana Pozner |
| collection | DOAJ |
| description | Mutations in SPG11 cause a complicated autosomal recessive form of hereditary spastic paraplegia (HSP). Mechanistically, there are indications for the dysregulation of the GSK3β/βCat signaling pathway in SPG11. In this study, we tested the therapeutic potential of the GSK3β inhibitor, tideglusib, to rescue neurodegeneration associated characteristics in an induced pluripotent stem cells (iPSCs) derived neuronal model from SPG11 patients and matched healthy controls as well as a CRISPR-Cas9 mediated SPG11 knock-out line and respective control. SPG11-iPSC derived cortical neurons, as well as the genome edited neurons exhibited shorter and less complex neurites than controls. Administration of tideglusib to these lines led to the rescue of neuritic impairments. Moreover, the treatment restored increased cell death and ameliorated the membranous inclusions in iPSC derived SPG11 neurons. Our results provide a first evidence for the rescue of neurite pathology in SPG11-HSP by tideglusib. The current lack of disease-modifying treatments for SPG11 and related types of complicated HSP renders tideglusib a candidate compound for future clinical application. |
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| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-12T23:17:19Z |
| publishDate | 2018-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-aa05080c772d4c9388bcf30d5a7732d82022-12-22T00:08:25ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2018-12-011210.3389/fnins.2018.00914415211Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical NeuronsTatyana Pozner0Annika Schray1Martin Regensburger2Martin Regensburger3Martin Regensburger4Dieter Chichung Lie5Ursula Schlötzer-Schrehardt6Jürgen Winkler7Jürgen Winkler8Soeren Turan9Soeren Turan10Beate Winner11Beate Winner12Department of Stem Cell Biology, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, GermanyDepartment of Stem Cell Biology, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, GermanyDepartment of Stem Cell Biology, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, GermanyDepartment of Neurology, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, GermanyDepartment of Molecular Neurology, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, GermanyInstitute of Biochemistry, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, GermanyDepartment of Ophthalmology, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, GermanyDepartment of Molecular Neurology, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, GermanyCenter of Rare Diseases Erlangen, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, GermanyDepartment of Stem Cell Biology, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, GermanyInstitute of Biochemistry, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, GermanyDepartment of Stem Cell Biology, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, GermanyCenter of Rare Diseases Erlangen, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, GermanyMutations in SPG11 cause a complicated autosomal recessive form of hereditary spastic paraplegia (HSP). Mechanistically, there are indications for the dysregulation of the GSK3β/βCat signaling pathway in SPG11. In this study, we tested the therapeutic potential of the GSK3β inhibitor, tideglusib, to rescue neurodegeneration associated characteristics in an induced pluripotent stem cells (iPSCs) derived neuronal model from SPG11 patients and matched healthy controls as well as a CRISPR-Cas9 mediated SPG11 knock-out line and respective control. SPG11-iPSC derived cortical neurons, as well as the genome edited neurons exhibited shorter and less complex neurites than controls. Administration of tideglusib to these lines led to the rescue of neuritic impairments. Moreover, the treatment restored increased cell death and ameliorated the membranous inclusions in iPSC derived SPG11 neurons. Our results provide a first evidence for the rescue of neurite pathology in SPG11-HSP by tideglusib. The current lack of disease-modifying treatments for SPG11 and related types of complicated HSP renders tideglusib a candidate compound for future clinical application.https://www.frontiersin.org/article/10.3389/fnins.2018.00914/fullinduced pluripotent stem cellneuronal cultureSPG11tideglusibGSK3β inhibitorhereditary spastic paraplegia |
| spellingShingle | Tatyana Pozner Annika Schray Martin Regensburger Martin Regensburger Martin Regensburger Dieter Chichung Lie Ursula Schlötzer-Schrehardt Jürgen Winkler Jürgen Winkler Soeren Turan Soeren Turan Beate Winner Beate Winner Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons Frontiers in Neuroscience induced pluripotent stem cell neuronal culture SPG11 tideglusib GSK3β inhibitor hereditary spastic paraplegia |
| title | Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons |
| title_full | Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons |
| title_fullStr | Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons |
| title_full_unstemmed | Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons |
| title_short | Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons |
| title_sort | tideglusib rescues neurite pathology of spg11 ipsc derived cortical neurons |
| topic | induced pluripotent stem cell neuronal culture SPG11 tideglusib GSK3β inhibitor hereditary spastic paraplegia |
| url | https://www.frontiersin.org/article/10.3389/fnins.2018.00914/full |
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