The X-linked intellectual disability gene CUL4B is critical for memory and synaptic function
Abstract Cullin 4B (CUL4B) is the scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Loss-of-function mutations in the human CUL4B gene lead to syndromic X-linked intellectual disability (XLID). Till now, the mechanism of intellectual disability caused by CUL4B mutation still ne...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-12-01
|
| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-024-01903-y |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846136772394745856 |
|---|---|
| author | Wei Jiang Jian Zhang Molin Wang Yongxin Zou Qiao Liu Yu Song Gongping Sun Yaoqin Gong Fan Zhang Baichun Jiang |
| author_facet | Wei Jiang Jian Zhang Molin Wang Yongxin Zou Qiao Liu Yu Song Gongping Sun Yaoqin Gong Fan Zhang Baichun Jiang |
| author_sort | Wei Jiang |
| collection | DOAJ |
| description | Abstract Cullin 4B (CUL4B) is the scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Loss-of-function mutations in the human CUL4B gene lead to syndromic X-linked intellectual disability (XLID). Till now, the mechanism of intellectual disability caused by CUL4B mutation still needs to be elucidated. In this study, we used single-nucleus RNA sequencing (snRNA-seq) to investigate the impact of CUL4B deficiency on the transcriptional programs of diverse cell types. The results revealed that depletion of CUL4B resulted in impaired intercellular communication and elicited cell type-specific transcriptional changes relevant to synapse dysfunction. Golgi-Cox staining of brain slices and immunostaining of in vitro cultured neurons revealed remarkable synapse loss in CUL4B-deficient mice. Ultrastructural analysis via transmission electron microscopy (TEM) showed that the width of the synaptic cleft was significantly greater in CUL4B-deficient mice. Electrophysiological experiments found a decrease in the amplitude of AMPA receptor-mediated EPSCs in the hippocampal CA1 pyramidal neurons of CUL4B-deficient mice. These results indicate that depletion of CUL4B in mice results in morphological and functional abnormalities in synapses. Furthermore, behavioral tests revealed that depletion of CUL4B in the mouse nervous system results in impaired spatial learning and memory. Taken together, the findings of this study reveal the pathogenesis of neurological disorders associated with CUL4B mutations and promote the identification of therapeutic targets that can halt synaptic abnormalities and preserve memory in individuals. |
| format | Article |
| id | doaj-art-7303f0706b2f4cc4b923520a88bb31f2 |
| institution | Kabale University |
| issn | 2051-5960 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-7303f0706b2f4cc4b923520a88bb31f22024-12-08T12:48:41ZengBMCActa Neuropathologica Communications2051-59602024-12-0112111910.1186/s40478-024-01903-yThe X-linked intellectual disability gene CUL4B is critical for memory and synaptic functionWei Jiang0Jian Zhang1Molin Wang2Yongxin Zou3Qiao Liu4Yu Song5Gongping Sun6Yaoqin Gong7Fan Zhang8Baichun Jiang9The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityThe Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityThe Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityThe Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityThe Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityThe Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityThe Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityThe Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityMedical Morphology Teaching Laboratory, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityThe Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityAbstract Cullin 4B (CUL4B) is the scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Loss-of-function mutations in the human CUL4B gene lead to syndromic X-linked intellectual disability (XLID). Till now, the mechanism of intellectual disability caused by CUL4B mutation still needs to be elucidated. In this study, we used single-nucleus RNA sequencing (snRNA-seq) to investigate the impact of CUL4B deficiency on the transcriptional programs of diverse cell types. The results revealed that depletion of CUL4B resulted in impaired intercellular communication and elicited cell type-specific transcriptional changes relevant to synapse dysfunction. Golgi-Cox staining of brain slices and immunostaining of in vitro cultured neurons revealed remarkable synapse loss in CUL4B-deficient mice. Ultrastructural analysis via transmission electron microscopy (TEM) showed that the width of the synaptic cleft was significantly greater in CUL4B-deficient mice. Electrophysiological experiments found a decrease in the amplitude of AMPA receptor-mediated EPSCs in the hippocampal CA1 pyramidal neurons of CUL4B-deficient mice. These results indicate that depletion of CUL4B in mice results in morphological and functional abnormalities in synapses. Furthermore, behavioral tests revealed that depletion of CUL4B in the mouse nervous system results in impaired spatial learning and memory. Taken together, the findings of this study reveal the pathogenesis of neurological disorders associated with CUL4B mutations and promote the identification of therapeutic targets that can halt synaptic abnormalities and preserve memory in individuals.https://doi.org/10.1186/s40478-024-01903-yCUL4BMemorySynapseIntellectual disability |
| spellingShingle | Wei Jiang Jian Zhang Molin Wang Yongxin Zou Qiao Liu Yu Song Gongping Sun Yaoqin Gong Fan Zhang Baichun Jiang The X-linked intellectual disability gene CUL4B is critical for memory and synaptic function Acta Neuropathologica Communications CUL4B Memory Synapse Intellectual disability |
| title | The X-linked intellectual disability gene CUL4B is critical for memory and synaptic function |
| title_full | The X-linked intellectual disability gene CUL4B is critical for memory and synaptic function |
| title_fullStr | The X-linked intellectual disability gene CUL4B is critical for memory and synaptic function |
| title_full_unstemmed | The X-linked intellectual disability gene CUL4B is critical for memory and synaptic function |
| title_short | The X-linked intellectual disability gene CUL4B is critical for memory and synaptic function |
| title_sort | x linked intellectual disability gene cul4b is critical for memory and synaptic function |
| topic | CUL4B Memory Synapse Intellectual disability |
| url | https://doi.org/10.1186/s40478-024-01903-y |
| work_keys_str_mv | AT weijiang thexlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT jianzhang thexlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT molinwang thexlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT yongxinzou thexlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT qiaoliu thexlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT yusong thexlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT gongpingsun thexlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT yaoqingong thexlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT fanzhang thexlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT baichunjiang thexlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT weijiang xlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT jianzhang xlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT molinwang xlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT yongxinzou xlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT qiaoliu xlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT yusong xlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT gongpingsun xlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT yaoqingong xlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT fanzhang xlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction AT baichunjiang xlinkedintellectualdisabilitygenecul4biscriticalformemoryandsynapticfunction |