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ZCCHC17 is a master regulator of synaptic gene expression in Alzheimer's disease.

ABSTRACT: Motivation:In an effort to better understand the molecular drivers of synaptic and neurophysiologic dysfunction in Alzheimer's disease (AD), we analyzed neuronal gene expression data from human AD brain tissue to identify master regulators of synaptic gene expression. Results:Master regulator analysis identifies ZCCHC17 as normally supporting the expression of a network of synaptic genes, and predicts that ZCCHC17 dysfunction in AD leads to lower expression of these genes. We demonstrate that ZCCHC17 is normally expressed in neurons and is reduced early in the course of AD pathology. We show that ZCCHC17 loss in rat neurons leads to lower expression of the majority of the predicted synaptic targets and that ZCCHC17 drives the expression of a similar gene network in humans and rats. These findings support a conserved function for ZCCHC17 between species and identify ZCCHC17 loss as an important early driver of lower synaptic gene expression in AD. Availability and implementation:Matlab and R scripts used in this paper are available at https://github.com/afteich/AD_ZCC. Contact:aft25@cumc.columbia.edu. Supplementary information:Supplementary data are available at Bioinformatics online.

SUBMITTER: Tomljanovic Z

PROVIDER: S-EPMC5860362 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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ZCCHC17 is a master regulator of synaptic gene expression in Alzheimer's disease.

Tomljanovic Zeljko Z Patel Mitesh M Shin William W Califano Andrea A Teich Andrew F AF

Bioinformatics (Oxford, England) 20180201 3

<h4>Motivation</h4>In an effort to better understand the molecular drivers of synaptic and neurophysiologic dysfunction in Alzheimer's disease (AD), we analyzed neuronal gene expression data from human AD brain tissue to identify master regulators of synaptic gene expression.<h4>Results</h4>Master regulator analysis identifies ZCCHC17 as normally supporting the expression of a network of synaptic genes, and predicts that ZCCHC17 dysfunction in AD leads to lower expression of these genes. We demo ...[more]

PMID: 29028963

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Project description:s 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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ZCCHC17 is a master regulator of synaptic gene expression in Alzheimer's disease.

Publications

ZCCHC17 is a master regulator of synaptic gene expression in Alzheimer's disease.

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