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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE203311 | GEO | 2022/06/30

REPOSITORIES: GEO

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Project description:As synapse degeneration is an early event in Alzheimer’s disease (AD) pathophysiology, a biofluid marker of synapse loss in living patients could be a surrogate marker of disease prognosis and therefore would be an excellent addition to the AD biomarker arsenal. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins that could be potential biomarkers of underlying synapse degeneration. The aim of this study was to identify, verify and evaluate a set of synaptic proteins as surrogate CSF markers of underlying synapse loss in AD patients. In the Discovery Stage, we combined high-throughput shotgun proteomics of the CSF with an exhaustive search of the literature and public databases for proteomic studies of the CSF and synapse. A thorough characterization of the synaptic component of the CSF identified 210 synaptic proteins that are detectable in human CSF. We selected an initial panel of 22 candidate biomarkers for evaluation. In the Verification Stage, 12 proteins were discarded due to poor detection by targeted mass spectrometry (Selected Reaction Monitoring, SRM). We confirmed the expression of the remaining 10 proteins either directly at (Calsynytenin-1, GluR2, GluR4, Neurexins 2A and 3A, Neuroligin-2, Syntaxin-1B, Thy-1 and Vamp-2), or surrounding (Tenascin-R), the human synapse using Array Tomography microscopy and biochemical fractionation methods. We quantified the synaptic panel by SRM in CSF samples from 2 independent clinical cohorts of cognitively normal controls and all clinical stages of AD (n=140). A set of the panel proteins demonstrated a non-linear profile distinct to that of existing biomarkers whereby the CSF levels were decreased at the earliest preclinical stage of AD, reflecting reduced synaptic density in these asymptomatic individuals and elevated at later symptomatic stages when neurodegeneration is widespread. In conclusion, we have identified a set of novel synapse-specific proteins that could have clinical value for assessing disease progression in individuals at-risk for AD and potentially in other neurological disorders characterized by early synapse loss.

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

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