Membrane remodeling by FAM92A1 during brain development regulates neuronal morphology, synaptic function, and cognition

Liang Wang, Ziyun Yang, Fudo Satoshi, Xavier Prasanna, Ziyi Yan, Helena Vihinen, Yaxing Chen, Yue Zhao, Xiumei He, Qian Bu, Hongchun Li, Ying Zhao, Linhong Jiang, Feng Qin, Yanping Dai, Ni Zhang, Meng Qin, Weihong Kuang, Yinglan Zhao, Eija Jokitalo, Ilpo Vattulainen, Tommi Kajander, Hongxia Zhao () and Xiaobo Cen ()
Additional contact information
Liang Wang: West China Hospital of Sichuan University
Ziyun Yang: West China Hospital of Sichuan University
Fudo Satoshi: University of Helsinki
Xavier Prasanna: University of Helsinki
Ziyi Yan: University of Helsinki
Helena Vihinen: University of Helsinki
Yaxing Chen: West China Hospital of Sichuan University
Yue Zhao: West China Hospital of Sichuan University
Xiumei He: West China Hospital of Sichuan University
Qian Bu: West China Hospital of Sichuan University
Hongchun Li: West China Hospital of Sichuan University
Ying Zhao: West China Hospital of Sichuan University
Linhong Jiang: West China Hospital of Sichuan University
Feng Qin: West China Hospital of Sichuan University
Yanping Dai: West China Hospital of Sichuan University
Ni Zhang: Sichuan University
Meng Qin: West China Hospital of Sichuan University
Weihong Kuang: Sichuan University
Yinglan Zhao: West China Hospital of Sichuan University
Eija Jokitalo: University of Helsinki
Ilpo Vattulainen: University of Helsinki
Tommi Kajander: University of Helsinki
Hongxia Zhao: University of Helsinki
Xiaobo Cen: West China Hospital of Sichuan University

Nature Communications, 2024, vol. 15, issue 1, 1-30

Abstract: Abstract The Bin/Amphiphysin/Rvs (BAR) domain protein FAM92A1 is a multifunctional protein engaged in regulating mitochondrial ultrastructure and ciliogenesis, but its physiological role in the brain remains unclear. Here, we show that FAM92A1 is expressed in neurons starting from embryonic development. FAM92A1 knockout in mice results in altered brain morphology and age-associated cognitive deficits, potentially due to neuronal degeneration and disrupted synaptic plasticity. Specifically, FAM92A1 deficiency impairs diverse neuronal membrane morphology, including the mitochondrial inner membrane, myelin sheath, and synapses, indicating its roles in membrane remodeling and maintenance. By determining the crystal structure of the FAM92A1 BAR domain, combined with atomistic molecular dynamics simulations, we uncover that FAM92A1 interacts with phosphoinositide- and cardiolipin-containing membranes to induce lipid-clustering and membrane curvature. Altogether, these findings reveal the physiological role of FAM92A1 in the brain, highlighting its impact on synaptic plasticity and neural function through the regulation of membrane remodeling and endocytic processes.

Date: 2024
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DOI: 10.1038/s41467-024-50565-w

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