PAK2 Haploinsufficiency Results in Synaptic Cytoskeleton Impairment and Autism-Related Behavior.


Journal Article

Synaptic cytoskeleton dysfunction represents a common pathogenesis in neurodevelopmental disorders, such as autism spectrum disorder (ASD). The serine/threonine kinase PAK2 is a critical regulator of cytoskeleton dynamics. However, its function within the central nervous system and its role in ASD pathogenesis remain undefined. Here, we found that Pak2 haploinsufficiency resulted in markedly decreased synapse densities, defective long-term potentiation, and autism-related behaviors in mice. Phosphorylation levels of key actin regulators LIMK1 and cofilin, together with their mediated actin polymerization, were reduced in Pak2+/-mice. We identified one de novo PAK2 nonsense mutation that impaired PAK2 function in vitro and in vivo and four de novo copy-number deletions containing PAK2 in large cohorts of patients with ASD. PAK2 deficiency extensively perturbed functional networks associated with ASD by regulating actin cytoskeleton dynamics. Our genetic and functional results demonstrate a critical role of PAK2 in brain development and autism pathogenesis.

Full Text

Duke Authors

Cited Authors

  • Wang, Y; Zeng, C; Li, J; Zhou, Z; Ju, X; Xia, S; Li, Y; Liu, A; Teng, H; Zhang, K; Shi, L; Bi, C; Xie, W; He, X; Jia, Z; Jiang, Y; Cai, T; Wu, J; Xia, K; Sun, ZS

Published Date

  • August 21, 2018

Published In

Volume / Issue

  • 24 / 8

Start / End Page

  • 2029 - 2041

PubMed ID

  • 30134165

Pubmed Central ID

  • 30134165

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2018.07.061


  • eng

Conference Location

  • United States