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Impaired differentiation of human induced neural stem cells by TOR1A overexpression

Please always quote using this URN: urn:nbn:de:bvb:20-opus-241177
  • DYT-TOR1A is the most common inherited dystonia caused by a three nucleotide (GAG) deletion (dE) in the TOR1A gene. Death early after birth and cortical anomalies of the full knockout in rodents underscore its developmental importance. We therefore explored the timed effects of TOR1A-wt and TOR1A-dE during differentiation in a human neural in vitro model. We used lentiviral tet-ON expression of TOR1A-wt and -dE in induced neural stem cells derived from healthy donors. Overexpression was induced during proliferation of neural precursors, duringDYT-TOR1A is the most common inherited dystonia caused by a three nucleotide (GAG) deletion (dE) in the TOR1A gene. Death early after birth and cortical anomalies of the full knockout in rodents underscore its developmental importance. We therefore explored the timed effects of TOR1A-wt and TOR1A-dE during differentiation in a human neural in vitro model. We used lentiviral tet-ON expression of TOR1A-wt and -dE in induced neural stem cells derived from healthy donors. Overexpression was induced during proliferation of neural precursors, during differentiation and after differentiation into mature neurons. Overexpression of both wildtype and mutated protein had no effect on the viability and cell number of neural precursors as well as mature neurons when initiated before or after differentiation. However, if induced during differentiation, overexpression of TOR1A-wt and -dE led to a pronounced reduction of mature neurons in a dose dependent manner. Our data underscores the importance of physiological expression levels of TOR1A as crucial for proper neuronal differentiation. We did not find evidence for a specific impact of the mutated TOR1A on neuronal maturation.show moreshow less

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Metadaten
Author: Felix Stengel, Franca Vulinovic, Britta Meier, Karen Grütz, Christine Klein, Philipp Capetian
URN:urn:nbn:de:bvb:20-opus-241177
Document Type:Journal article
Faculties:Medizinische Fakultät / Neurologische Klinik und Poliklinik
Language:English
Parent Title (English):Molecular Biology Reports
Year of Completion:2020
Volume:47
Pagenumber:3993–4001
Source:Molecular Biology Reports 47, 3993–4001 (2020). https://doi.org/10.1007/s11033-020-05390-x
URL:https://doi.org/10.1007/s11033-020-05390-x
DOI:https://doi.org/10.25972/OPUS-24117
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:DYT1; TOR1A; dystonia; inducible expression; neuronal differentiation; neuronal stem cells; torsinA
Release Date:2021/07/05
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International