Disruption of dynactin complex function in intellectual disability

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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2026-06-30
DOI
https://doi.org/10.1073/pnas.2522636123
Primary Topic
Microtubule and mitosis dynamics
Type
article
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article

Disruption of dynactin complex function in intellectual disability

Luonan Chen, Yuxiang Pan, Zhuo Li, Ping Hu et al.
Proceedings of the National Academy of Sciences
Microtubule and mitosis dynamics
article

Disruption of dynactin complex function in intellectual disability

Luonan Chen, Yuxiang Pan, Zhuo Li, Ping Hu, Lingqian Wu, Yonghua Zhao, Mingchun Liao, Yun Stone Shi, Bin Wang, Jie Yang, Lan Bao, Qiu Wang, Tianyun Wang, Huijuan Li, Xu Zhang, Dandan Zheng, Xiaoli Rao
article en

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.

Proceedings of the National Academy of SciencesVol. 123(27)
Peking University (CN), University of Macau (MO), Guangdong Polytechnic of Science and Technology (CN), Nanjing Maternity and Child Health Care Hospital (CN), Ministry of Education (ME), Medical Genetics Center (DE), Center for Excellence in Molecular Cell Science (CN), Quality Research (US), Ministry of Education and Child Care (CA), Center for Autism and Related Disorders (US)
Gender equality
Openalex Percentile: Top 10%
Microtubule and mitosis dynamics
DOIOpen Access PDFOpenAlex
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