Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen 518036, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
Cell Rep. 2022 Jul 19;40(3):111101. doi: 10.1016/j.celrep.2022.111101.
Synapse loss and memory decline are the primary features of neurodegenerative dementia. However, the molecular underpinnings that drive memory loss remain largely unknown. Here, we report that FAM69C is a kinase critically involved in neurodegenerative dementia. Biochemical analyses uncover that FAM69C is a serine/threonine kinase. We generate the Fam69c knockout mice and show by single-cell RNA sequencing that FAM69C deficiency drives cell-type-specific transcriptional changes relevant to synapse dysfunction. Electrophysiological, morphological, and behavioral experiments demonstrate impairments in synaptic plasticity, dendritic spine density, and memory in Fam69c knockout mice, as well as stress-induced neuronal death. Phosphoproteomic characterizations reveal that FAM69C substrates are involved in synaptic structure and function. Finally, reduced levels of FAM69C are found in postmortem brains of Alzheimer's disease patients. Our study demonstrates that FAM69C is a protective regulator of memory and suggests FAM69C as a potential therapeutic target for memory loss in neurodegenerative dementia.
突触丢失和记忆衰退是神经退行性痴呆的主要特征。然而，导致记忆丧失的分子基础在很大程度上仍然未知。在这里，我们报告 FAM69C 是一种与神经退行性痴呆密切相关的激酶。生化分析揭示 FAM69C 是一种丝氨酸/苏氨酸激酶。我们生成了 Fam69c 基因敲除小鼠，并通过单细胞 RNA 测序表明 FAM69C 缺乏会导致与突触功能障碍相关的细胞类型特异性转录变化。电生理、形态和行为学实验表明 Fam69c 基因敲除小鼠在突触可塑性、树突棘密度和记忆方面存在缺陷，以及应激诱导的神经元死亡。磷酸蛋白质组学特征表明 FAM69C 的底物参与突触结构和功能。最后，在阿尔茨海默病患者的尸检大脑中发现 FAM69C 的水平降低。我们的研究表明 FAM69C 是记忆的保护性调节因子，并提示 FAM69C 可能是神经退行性痴呆中记忆丧失的潜在治疗靶点。
