Wang Xiaojie, Wang Liang, Bu Qian, Xiao Yuzhou, Zhao Yue, Jiang Linhong, Dai Yanping, Li Hongchun, Liu Haxiaoyu, Chen Yaxing, Flores Angelo D, Zhao Yinglan, Cen Xiaobo
Mental Health Center and National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Neuroscience, City University of Hong Kong, Hong Kong 999077, China.
J Neurosci. 2025 May 14;45(20):e1867242025. doi: 10.1523/JNEUROSCI.1867-24.2025.
Leucine zipper protein 1 (LUZP1) functions in the maintenance and dynamics of the cytoskeleton by interacting with actin and microtubules. Deficiency or mutation of LUZP1 is associated with brain developmental disorders; however, its precise role in brain function remains unclear. We showed that LUZP1 localizes to actin and is highly expressed in CaMKIIα-expressing neurons within the mouse hippocampal dentate gyrus. Depletion of LUZP1 impedes dendritic spine maturation, which is characterized by excess immature filopodia and loss of mature mushroom spines both in vitro and in vivo. LUZP1 knockdown reduces spontaneous electrical activity and synaptic plasticity in hippocampal neurons. Conditional deletion of LUZP1 in CaMKIIα-expressing neurons causes impaired learning and memory behavior in mice of both sexes. Mechanistically, LUZP1 control dendritic maturation by directly interacting with filamin A and modulating the Rac1-PAK1 signaling pathway. These findings shed light on the role of LUZP1 in regulating synaptic plasticity and brain function.
亮氨酸拉链蛋白1（LUZP1）通过与肌动蛋白和微管相互作用，在细胞骨架的维持和动态变化中发挥作用。LUZP1的缺乏或突变与脑发育障碍有关；然而，其在脑功能中的精确作用仍不清楚。我们发现LUZP1定位于肌动蛋白，并且在小鼠海马齿状回中表达钙/钙调蛋白依赖性蛋白激酶IIα（CaMKIIα）的神经元中高度表达。LUZP1的缺失会阻碍树突棘成熟，其特征是在体外和体内均出现过多的未成熟丝状伪足和成熟蘑菇状棘的丢失。敲低LUZP1会降低海马神经元的自发电活动和突触可塑性。在表达CaMKIIα的神经元中条件性缺失LUZP1会导致雌雄小鼠的学习和记忆行为受损。从机制上讲，LUZP1通过直接与细丝蛋白A相互作用并调节Rac1-PAK1信号通路来控制树突成熟。这些发现揭示了LUZP1在调节突触可塑性和脑功能中的作用。
