Disruption of dynactin complex function in intellectual disability
Abstract
Intellectual disability (ID) is a highly prevalent condition affecting approximately 200 millions of people worldwide, characterized by impaired cognitive function. Dynactin complex consists of multiple protein subunits and is required for intracellular trafficking and synaptic homeostasis in developing and mature neurons. Here, we identify deleterious variants of dynactin subunit 4 (DCTN4) in ID pedigrees. DCTN4 ablation in mice results in altered neuronal positioning and apoptosis in neural progenitor cells. Notably, mice carrying the ID-linked DCTN4 variant exhibit cognitive deficits with impaired dendritic development. Cortical neurons with DCTN4 deficiency or variant show reduced levels of various dynactin subunits, suggesting that deficits in dynactin complex affects synaptic function. Furthermore, disruption of the DCTN4–JIP3 complex impairs lysosomal transport and dendritic development as well as synaptic development. Importantly, we showed that damaging variants in another dynactin subunit DCTN2 also disrupt neuronal positioning, reinforcing the critical role of dynactin complex in neurodevelopment and ID pathogenesis. These findings illustrate dysfunctional dynactin complex as a previously unrecognized disease mechanism of ID.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Yuxiang Pan
Guangdong Institute of Intelligence Science and Technology
Huijuan Li
Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics, Ministry of Education Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University
Mingchun Liao
Guangdong Institute of Intelligence Science and Technology
Tianyun Wang
Department of Medical Genetics, School of Basic Medical Sciences, Neuroscience Research Institute, Key Laboratory for Neuroscience, Ministry of Education of China & National Health Commission of China, Peking University
Xiaoli Rao
Department of Medical Genetics, School of Basic Medical Sciences, Neuroscience Research Institute, Key Laboratory for Neuroscience, Ministry of Education of China & National Health Commission of China, Peking University
Qiu Wang
Ping Hu
Dandan Zheng
Guangdong Institute of Intelligence Science and Technology
Yang Jiao
Luonan Chen
Yun Stone Shi
Guangdong Institute of Intelligence Science and Technology
Yonghua Zhao
Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau
Xu Zhang
Zhuo Li
Lan Bao
Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, the Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Lingqian Wu
Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics, Ministry of Education Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University
Bin Wang