Neurodegenerative diseases are mainly characterized by progressive cognitive dysfunction and abnormal behavior, which seriously affect the working ability and quality of life of patients. Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases, and its incidence is increasing with the aging process, increasing the social and economic burden. At present, there is no effective preventive method, and limited drug treatment cannot improve the gradually declining cognitive function of patients. Therefore, studying the mechanisms of memory loss in Alzheimer’s disease is an important issue in the field of neuroscience.
On July 19, 2022, the team of Professor Yuxin Yin from the Institute of Systems Biomedicine of Peking University and the team of Professor Jianping Jia from Xuanwu Hospital published a research paper entitled“ FAM69C, a kinase critical for synaptic function and memory, is defective in neurodegenerative dementia” in the Cell Reports journal.
This study identified a novel serine/threonine protein kinase FAM69C, explained its role in the regulation of synaptic plasticity and memory, and revealed that abnormal FAM69C protein plays an important role in the process of memory loss in Alzheimer’s disease.
The team members found that the highly expressed FAM69C protein in the brain has potential kinase structure characteristics by screening the protein tissue distribution specificity, aligning the catalytic sequences of the kinases and analyzing the three-dimensional structure of the active center. FAM69C was confirmed to be a novel serine/threonine kinase by phosphorylation mass spectrometry and in vitro phosphorylation experiments.
Fam69c knockout mice were constructed to study the biological function of FAM69C . Single-cell transcriptome sequencing revealed that loss of FAM69C resulted in a marked decline in biological pathways regulating synaptic structure and function in neurons and glia. Using neuroelectrophysiological, morphological, and behavioral approaches, we found that FAM69C knockout disrupted synaptic plasticity, decreased synaptic number, led to memory loss, and exhibited neurodegenerative changes in response to conditioned stimulation. A series of phosphorylated substrates and binding proteins of FAM69C were identified by phosphorylation mass spectrometry and protein profiling, and pathway enrichment analysis suggested that potential substrates were involved in synaptic structural composition and synaptic transmission.
Furthermore, the kinase activity assay confirmed that FAM69C autophosphorylates at S51 and phosphorylates synaptic protein Amphyphysin at T445 and S654. Finally, FAM69C pathological aggregation and significantly decreased expression levels were observed in Alzheimer’s disease patient brains.
Taken together, this study identifies FAM69C, a protein kinase involved in the development and progression of Alzheimer’s disease, expanding the human kinome. Functional studies reveal that FAM69C plays a protective role in synaptic function, neuronal activity, and memory processes. Thus, the study uncovered a new mechanism of memory loss in neurodegenerative dementia.
Fan Mei , a lecturer at Peking University School of Basic Medicine, and Jiapan Hu, a postdoctoral fellow at Peking University Shenzhen Hospital are the co-first authors of the article, and Professor Yuxin Yin from the Institute of Systems Biomedicine of Peking University and Professor Jianping Jia from Xuanwu Hospital are the co-corresponding authors. The research was supported by the National Key R&D Program, the National Natural Science Foundation of China, and the National Natural Science Foundation of China.