Autism-linked mutations of CTTNBP2 reduce social interaction and impair dendritic spine formation via diverse mechanisms

Acta Neuropathologica Communications

Chiu-An Lo¹  Brian E. Chen²  Bing-Yuan Hsieh³  Ching-Yen Tsai³  Pu-Yun Shih⁴  Yi-Ping Hsueh⁴ 

[1] Centre for Research in Neuroscience, McGill University Health Centre, Montreal General Hospital, H3G 1A4, Montréal, QC, Canada;Centre for Research in Neuroscience, McGill University Health Centre, Montreal General Hospital, H3G 1A4, Montréal, QC, Canada;Departments of Medicine and Neurology & Neurosurgery, McGill University, Montréal, QC, Canada;Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, ROC;Molecular and Cell Biology, Taiwan International Graduate Program, Institute of Molecular Biology, Academia Sinica and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC;Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, ROC;

关键词: Autism spectrum disorder;    Cortactin;    Dendritic spine formation;    F-actin;    Microtubule;   

DOI  :  10.1186/s40478-020-01053-x

来源: Springer

【 摘 要 】

Abnormal synaptic formation and signaling is one of the key molecular features of autism spectrum disorders (ASD). Cortactin binding protein 2 (CTTNBP2), an ASD-linked gene, is known to regulate the subcellular distribution of synaptic proteins, such as cortactin, thereby controlling dendritic spine formation and maintenance. However, it remains unclear how ASD-linked mutations of CTTNBP2 influence its function. Here, using cultured hippocampal neurons and knockin mouse models, we screen seven ASD-linked mutations in the short form of the Cttnbp2 gene and identify that M120I, R533* and D570Y mutations impair CTTNBP2 protein–protein interactions via divergent mechanisms to reduce dendritic spine density in neurons. R533* mutation impairs CTTNBP2 interaction with cortactin due to lack of the C-terminal proline-rich domain. Through an N–C terminal interaction, M120I mutation at the N-terminal region of CTTNBP2 also negatively influences cortactin interaction. D570Y mutation increases the association of CTTNBP2 with microtubule, resulting in a dendritic localization of CTTNBP2, consequently reducing the distribution of CTTNBP2 in dendritic spines and impairing the synaptic function of CTTNBP2. Finally, we generated heterozygous M120I knockin mice to mimic the genetic variation of patients and found they exhibit reduced social interaction. Our study elucidates that different ASD-linked mutations of CTTNBP2 result in diverse molecular deficits, but all have the similar consequence of synaptic impairment.

【 授权许可】

CC BY