Reduced Expression of GABAA Receptor Alpha2 Subunit Is Associated With Disinhibition of DYT-THAP1 Dystonia Patient-Derived Striatal Medium Spiny Neurons
DYT-THAP1 dystonia (formerly DYT6) is an adolescent-onset dystonia characterized by involuntary muscle contractions usually involving the upper body. It is caused by mutations in the gene THAP1 encoding for the transcription factor Thanatos-associated protein (THAP) domain containing apoptosis-assoc...
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Frontiers Media S.A.
2021-05-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.650586/full |
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| author | Selma Staege Selma Staege Anna Kutschenko Hauke Baumann Hannes Glaß Lisa Henkel Lisa Henkel Thomas Gschwendtberger Thomas Gschwendtberger Norman Kalmbach Martin Klietz Andreas Hermann Andreas Hermann Katja Lohmann Philip Seibler Florian Wegner Florian Wegner |
| author_facet | Selma Staege Selma Staege Anna Kutschenko Hauke Baumann Hannes Glaß Lisa Henkel Lisa Henkel Thomas Gschwendtberger Thomas Gschwendtberger Norman Kalmbach Martin Klietz Andreas Hermann Andreas Hermann Katja Lohmann Philip Seibler Florian Wegner Florian Wegner |
| author_sort | Selma Staege |
| collection | DOAJ |
| description | DYT-THAP1 dystonia (formerly DYT6) is an adolescent-onset dystonia characterized by involuntary muscle contractions usually involving the upper body. It is caused by mutations in the gene THAP1 encoding for the transcription factor Thanatos-associated protein (THAP) domain containing apoptosis-associated protein 1 and inherited in an autosomal-dominant manner with reduced penetrance. Alterations in the development of striatal neuronal projections and synaptic function are known from transgenic mice models. To investigate pathogenetic mechanisms, human induced pluripotent stem cell (iPSC)-derived medium spiny neurons (MSNs) from two patients and one family member with reduced penetrance carrying a mutation in the gene THAP1 (c.474delA and c.38G > A) were functionally characterized in comparison to healthy controls. Calcium imaging and quantitative PCR analysis revealed significantly lower Ca2+ amplitudes upon GABA applications and a marked downregulation of the gene encoding the GABAA receptor alpha2 subunit in THAP1 MSNs indicating a decreased GABAergic transmission. Whole-cell patch-clamp recordings showed a significantly lower frequency of miniature postsynaptic currents (mPSCs), whereas the frequency of spontaneous action potentials (APs) was elevated in THAP1 MSNs suggesting that decreased synaptic activity might have resulted in enhanced generation of APs. Our molecular and functional data indicate that a reduced expression of GABAA receptor alpha2 subunit could eventually lead to limited GABAergic synaptic transmission, neuronal disinhibition, and hyperexcitability of THAP1 MSNs. These data give pathophysiological insight and may contribute to the development of novel treatment strategies for DYT-THAP1 dystonia. |
| first_indexed | 2024-12-16T11:01:47Z |
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| id | doaj.art-e430a2e0bfeb42c5b6f33e85eb50634e |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-16T11:01:47Z |
| publishDate | 2021-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-e430a2e0bfeb42c5b6f33e85eb50634e2022-12-21T22:33:59ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-05-01910.3389/fcell.2021.650586650586Reduced Expression of GABAA Receptor Alpha2 Subunit Is Associated With Disinhibition of DYT-THAP1 Dystonia Patient-Derived Striatal Medium Spiny NeuronsSelma Staege0Selma Staege1Anna Kutschenko2Hauke Baumann3Hannes Glaß4Lisa Henkel5Lisa Henkel6Thomas Gschwendtberger7Thomas Gschwendtberger8Norman Kalmbach9Martin Klietz10Andreas Hermann11Andreas Hermann12Katja Lohmann13Philip Seibler14Florian Wegner15Florian Wegner16Department of Neurology, Hannover Medical School, Hanover, GermanyCenter for Systems Neuroscience, Hanover, GermanyDepartment of Neurology, Hannover Medical School, Hanover, GermanyInstitute of Neurogenetics, University of Lübeck, Lübeck, GermanyTranslational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, University of Rostock, Rostock, GermanyDepartment of Neurology, Hannover Medical School, Hanover, GermanyCenter for Systems Neuroscience, Hanover, GermanyDepartment of Neurology, Hannover Medical School, Hanover, GermanyCenter for Systems Neuroscience, Hanover, GermanyDepartment of Neurology, Hannover Medical School, Hanover, GermanyDepartment of Neurology, Hannover Medical School, Hanover, GermanyTranslational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, University of Rostock, Rostock, GermanyGerman Center for Neurodegenerative Diseases Rostock/Greifswald, Rostock, GermanyInstitute of Neurogenetics, University of Lübeck, Lübeck, GermanyInstitute of Neurogenetics, University of Lübeck, Lübeck, GermanyDepartment of Neurology, Hannover Medical School, Hanover, GermanyCenter for Systems Neuroscience, Hanover, GermanyDYT-THAP1 dystonia (formerly DYT6) is an adolescent-onset dystonia characterized by involuntary muscle contractions usually involving the upper body. It is caused by mutations in the gene THAP1 encoding for the transcription factor Thanatos-associated protein (THAP) domain containing apoptosis-associated protein 1 and inherited in an autosomal-dominant manner with reduced penetrance. Alterations in the development of striatal neuronal projections and synaptic function are known from transgenic mice models. To investigate pathogenetic mechanisms, human induced pluripotent stem cell (iPSC)-derived medium spiny neurons (MSNs) from two patients and one family member with reduced penetrance carrying a mutation in the gene THAP1 (c.474delA and c.38G > A) were functionally characterized in comparison to healthy controls. Calcium imaging and quantitative PCR analysis revealed significantly lower Ca2+ amplitudes upon GABA applications and a marked downregulation of the gene encoding the GABAA receptor alpha2 subunit in THAP1 MSNs indicating a decreased GABAergic transmission. Whole-cell patch-clamp recordings showed a significantly lower frequency of miniature postsynaptic currents (mPSCs), whereas the frequency of spontaneous action potentials (APs) was elevated in THAP1 MSNs suggesting that decreased synaptic activity might have resulted in enhanced generation of APs. Our molecular and functional data indicate that a reduced expression of GABAA receptor alpha2 subunit could eventually lead to limited GABAergic synaptic transmission, neuronal disinhibition, and hyperexcitability of THAP1 MSNs. These data give pathophysiological insight and may contribute to the development of novel treatment strategies for DYT-THAP1 dystonia.https://www.frontiersin.org/articles/10.3389/fcell.2021.650586/fullDYT-THAP1genetic dystoniainduced pluripotent stem cellsstriatal medium spiny neuronsGABAA receptorcalcium dynamics |
| spellingShingle | Selma Staege Selma Staege Anna Kutschenko Hauke Baumann Hannes Glaß Lisa Henkel Lisa Henkel Thomas Gschwendtberger Thomas Gschwendtberger Norman Kalmbach Martin Klietz Andreas Hermann Andreas Hermann Katja Lohmann Philip Seibler Florian Wegner Florian Wegner Reduced Expression of GABAA Receptor Alpha2 Subunit Is Associated With Disinhibition of DYT-THAP1 Dystonia Patient-Derived Striatal Medium Spiny Neurons Frontiers in Cell and Developmental Biology DYT-THAP1 genetic dystonia induced pluripotent stem cells striatal medium spiny neurons GABAA receptor calcium dynamics |
| title | Reduced Expression of GABAA Receptor Alpha2 Subunit Is Associated With Disinhibition of DYT-THAP1 Dystonia Patient-Derived Striatal Medium Spiny Neurons |
| title_full | Reduced Expression of GABAA Receptor Alpha2 Subunit Is Associated With Disinhibition of DYT-THAP1 Dystonia Patient-Derived Striatal Medium Spiny Neurons |
| title_fullStr | Reduced Expression of GABAA Receptor Alpha2 Subunit Is Associated With Disinhibition of DYT-THAP1 Dystonia Patient-Derived Striatal Medium Spiny Neurons |
| title_full_unstemmed | Reduced Expression of GABAA Receptor Alpha2 Subunit Is Associated With Disinhibition of DYT-THAP1 Dystonia Patient-Derived Striatal Medium Spiny Neurons |
| title_short | Reduced Expression of GABAA Receptor Alpha2 Subunit Is Associated With Disinhibition of DYT-THAP1 Dystonia Patient-Derived Striatal Medium Spiny Neurons |
| title_sort | reduced expression of gabaa receptor alpha2 subunit is associated with disinhibition of dyt thap1 dystonia patient derived striatal medium spiny neurons |
| topic | DYT-THAP1 genetic dystonia induced pluripotent stem cells striatal medium spiny neurons GABAA receptor calcium dynamics |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.650586/full |
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