Increased degradation of FMRP contributes to neuronal hyperexcitability in tuberous sclerosis complex
Summary: Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, but new therapies have been impeded by a lack of understanding of the pathological mechanisms. Tuberous sclerosis complex (TSC) and fragile X syndrome are associated with alterations in the mechanistic target...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723008495 |
| _version_ | 1797731091540344832 |
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| author | Kellen D. Winden Truc T. Pham Nicole A. Teaney Juan Ruiz Ryan Chen Cidi Chen Mustafa Sahin |
| author_facet | Kellen D. Winden Truc T. Pham Nicole A. Teaney Juan Ruiz Ryan Chen Cidi Chen Mustafa Sahin |
| author_sort | Kellen D. Winden |
| collection | DOAJ |
| description | Summary: Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, but new therapies have been impeded by a lack of understanding of the pathological mechanisms. Tuberous sclerosis complex (TSC) and fragile X syndrome are associated with alterations in the mechanistic target of rapamycin (mTOR) and fragile X messenger ribonucleoprotein 1 (FMRP), which have been implicated in the development of ASD. Previously, we observed that transcripts associated with FMRP were down-regulated in TSC2-deficient neurons. In this study, we find that FMRP turnover is dysregulated in TSC2-deficient rodent primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons and is dependent on the E3 ubiquitin ligase anaphase-promoting complex. We also demonstrate that overexpression of FMRP can partially rescue hyperexcitability in TSC2-deficient iPSC-derived neurons. These data indicate that FMRP dysregulation represents an important pathological mechanism in the development of abnormal neuronal activity in TSC and illustrate a molecular convergence between these two neurogenetic disorders. |
| first_indexed | 2024-03-12T11:53:45Z |
| format | Article |
| id | doaj.art-70a2b2c8add248b4a5c39d56149e00ec |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T11:53:45Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-70a2b2c8add248b4a5c39d56149e00ec2023-08-31T05:01:49ZengElsevierCell Reports2211-12472023-08-01428112838Increased degradation of FMRP contributes to neuronal hyperexcitability in tuberous sclerosis complexKellen D. Winden0Truc T. Pham1Nicole A. Teaney2Juan Ruiz3Ryan Chen4Cidi Chen5Mustafa Sahin6Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USAHuman Neuron Core, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USAHuman Neuron Core, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; Corresponding authorSummary: Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, but new therapies have been impeded by a lack of understanding of the pathological mechanisms. Tuberous sclerosis complex (TSC) and fragile X syndrome are associated with alterations in the mechanistic target of rapamycin (mTOR) and fragile X messenger ribonucleoprotein 1 (FMRP), which have been implicated in the development of ASD. Previously, we observed that transcripts associated with FMRP were down-regulated in TSC2-deficient neurons. In this study, we find that FMRP turnover is dysregulated in TSC2-deficient rodent primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons and is dependent on the E3 ubiquitin ligase anaphase-promoting complex. We also demonstrate that overexpression of FMRP can partially rescue hyperexcitability in TSC2-deficient iPSC-derived neurons. These data indicate that FMRP dysregulation represents an important pathological mechanism in the development of abnormal neuronal activity in TSC and illustrate a molecular convergence between these two neurogenetic disorders.http://www.sciencedirect.com/science/article/pii/S2211124723008495CP: Neuroscience |
| spellingShingle | Kellen D. Winden Truc T. Pham Nicole A. Teaney Juan Ruiz Ryan Chen Cidi Chen Mustafa Sahin Increased degradation of FMRP contributes to neuronal hyperexcitability in tuberous sclerosis complex Cell Reports CP: Neuroscience |
| title | Increased degradation of FMRP contributes to neuronal hyperexcitability in tuberous sclerosis complex |
| title_full | Increased degradation of FMRP contributes to neuronal hyperexcitability in tuberous sclerosis complex |
| title_fullStr | Increased degradation of FMRP contributes to neuronal hyperexcitability in tuberous sclerosis complex |
| title_full_unstemmed | Increased degradation of FMRP contributes to neuronal hyperexcitability in tuberous sclerosis complex |
| title_short | Increased degradation of FMRP contributes to neuronal hyperexcitability in tuberous sclerosis complex |
| title_sort | increased degradation of fmrp contributes to neuronal hyperexcitability in tuberous sclerosis complex |
| topic | CP: Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723008495 |
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