Single-cell RNA sequencing of cortical samples in Fam69c knockout mice

Synapse loss and memory decline are the primary features of neurodegenerative dementia. However, molecular underpinnings that drive memory loss remain largely unknown. Here, we report that FAM69C is a novel kinase critically involved in neurodegenerative dementia. Biochemical analyses uncovered that FAM69C is a serine/threonine kinase. We generated the Fam69c knockout mice, and showed by single-cell RNA sequencing that FAM69C deficiency drives cell-type-specific transcriptional changes relevant to synapse dysfunction. Electrophysiological, morphological and behavioral experiments demonstrated impairments in synaptic plasticity, dendritic spine density and memory in Fam69c knockout mice, as well as stress-induced neuronal death. Phosphoproteomic characterizations revealed FAM69C substrates involved in synaptic structure and function. Finally, reduced levels of FAM69C were found in postmortem brains of AD. 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. Overall design: Study of cell-type-specific transcriptional changes in Fam69c wildtype and knockout cortical tissues using 10x Genomics platform.