Mimicking hypomethylation of FUS requires liquid–liquid phase separation to induce synaptic dysfunctions
Abstract The hypomethylation of fused in sarcoma (FUS) in frontotemporal lobar degeneration promotes the formation of irreversible condensates of FUS. However, the mechanisms by which these hypomethylated FUS condensates cause neuronal dysfunction are unknown. Here we report that expression of FUS c...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-12-01
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| Series: | Acta Neuropathologica Communications |
| Online Access: | https://doi.org/10.1186/s40478-023-01703-w |
| _version_ | 1797376737658535936 |
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| author | Seung Chan Kim Scott J. Mitchell Seema Qamar Daniel J. Whitcomb Marc-David Ruepp Peter St George-Hyslop Kwangwook Cho |
| author_facet | Seung Chan Kim Scott J. Mitchell Seema Qamar Daniel J. Whitcomb Marc-David Ruepp Peter St George-Hyslop Kwangwook Cho |
| author_sort | Seung Chan Kim |
| collection | DOAJ |
| description | Abstract The hypomethylation of fused in sarcoma (FUS) in frontotemporal lobar degeneration promotes the formation of irreversible condensates of FUS. However, the mechanisms by which these hypomethylated FUS condensates cause neuronal dysfunction are unknown. Here we report that expression of FUS constructs mimicking hypomethylated FUS causes aberrant dendritic FUS condensates in CA1 neurons. These hypomethylated FUS condensates exhibit spontaneous, and activity induced movement within the dendrite. They impair excitatory synaptic transmission, postsynaptic density-95 expression, and dendritic spine plasticity. These neurophysiological defects are dependent upon both the dendritic localisation of the condensates, and their ability to undergo liquid–liquid phase separation. These results indicate that the irreversible liquid–liquid phase separation is a key component of hypomethylated FUS pathophysiology in sporadic FTLD, and this can cause synapse dysfunction in sporadic FTLD. |
| first_indexed | 2024-03-08T19:44:01Z |
| format | Article |
| id | doaj.art-f1d094e7bd984d60b4f09d9494f5578d |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-08T19:44:01Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-f1d094e7bd984d60b4f09d9494f5578d2023-12-24T12:31:55ZengBMCActa Neuropathologica Communications2051-59602023-12-0111111510.1186/s40478-023-01703-wMimicking hypomethylation of FUS requires liquid–liquid phase separation to induce synaptic dysfunctionsSeung Chan Kim0Scott J. Mitchell1Seema Qamar2Daniel J. Whitcomb3Marc-David Ruepp4Peter St George-Hyslop5Kwangwook Cho6Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, UK-Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, King’s College LondonDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, UK-Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, King’s College LondonDepartment of Clinical Neurosciences, Cambridge Institute for Medical Research, University of CambridgeBristol Medical School, University of BristolDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, UK-Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, King’s College LondonDepartment of Clinical Neurosciences, Cambridge Institute for Medical Research, University of CambridgeDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, UK-Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, King’s College LondonAbstract The hypomethylation of fused in sarcoma (FUS) in frontotemporal lobar degeneration promotes the formation of irreversible condensates of FUS. However, the mechanisms by which these hypomethylated FUS condensates cause neuronal dysfunction are unknown. Here we report that expression of FUS constructs mimicking hypomethylated FUS causes aberrant dendritic FUS condensates in CA1 neurons. These hypomethylated FUS condensates exhibit spontaneous, and activity induced movement within the dendrite. They impair excitatory synaptic transmission, postsynaptic density-95 expression, and dendritic spine plasticity. These neurophysiological defects are dependent upon both the dendritic localisation of the condensates, and their ability to undergo liquid–liquid phase separation. These results indicate that the irreversible liquid–liquid phase separation is a key component of hypomethylated FUS pathophysiology in sporadic FTLD, and this can cause synapse dysfunction in sporadic FTLD.https://doi.org/10.1186/s40478-023-01703-w |
| spellingShingle | Seung Chan Kim Scott J. Mitchell Seema Qamar Daniel J. Whitcomb Marc-David Ruepp Peter St George-Hyslop Kwangwook Cho Mimicking hypomethylation of FUS requires liquid–liquid phase separation to induce synaptic dysfunctions Acta Neuropathologica Communications |
| title | Mimicking hypomethylation of FUS requires liquid–liquid phase separation to induce synaptic dysfunctions |
| title_full | Mimicking hypomethylation of FUS requires liquid–liquid phase separation to induce synaptic dysfunctions |
| title_fullStr | Mimicking hypomethylation of FUS requires liquid–liquid phase separation to induce synaptic dysfunctions |
| title_full_unstemmed | Mimicking hypomethylation of FUS requires liquid–liquid phase separation to induce synaptic dysfunctions |
| title_short | Mimicking hypomethylation of FUS requires liquid–liquid phase separation to induce synaptic dysfunctions |
| title_sort | mimicking hypomethylation of fus requires liquid liquid phase separation to induce synaptic dysfunctions |
| url | https://doi.org/10.1186/s40478-023-01703-w |
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