ZCCHC17 Knockdown Phenocopies Alzheimer's Disease-Related Loss of Synaptic Proteins and Hyperexcitability

Andrew F. Teich, MD, PhD

Synaptic dysfunction is a critical event in Alzheimer’s disease (AD) pathogenesis and synaptic loss correlates strongly with pre-mortem cognitive status. These structural changes are accompanied by large-scale dysregulation of synaptic gene expression in AD brain tissue, and these findings have been replicated in recent gene expression studies. Several therapeutic strategies based on rescuing synaptic dysfunction are currently being pursued, and the molecular basis for synaptic dysfunction in AD remains an outstanding question for the field.

Our group previously identified ZCCHC17 using a bioinformatic screen as a candidate driver of synaptic dysfunction in AD, and predicted that its activity is reduced in AD, leading to dysregulation of synaptic gene expression. Prior to our group’s interest in ZCCHC17, its function in the brain was unexplored, although it had been shown to have roles in both mRNA and rRNA processing in other tissues. After identifying ZCCHC17 as a candidate driver of synaptic dysfunction, we showed that ZCCHC17 protein is expressed in neurons and declines in AD brain tissue before significant gliosis or neuronal loss, and knockdown of ZCCHC17 in rat neuronal cultures leads to dysregulation of a wide range of genes, including synaptic genes. More recently, we have shown that ZCCHC17 regulates neuronal RNA splicing using human iPSC-derived neurons, and loss of ZCCHC17 may explain a portion of splicing abnormalities in AD brain tissue. Further, we have shown that CNS ZCCHC17 expression predicts cognitive resilience in the setting of AD pathology, and support for ZCCHC17 activity may therefore represent a therapeutic strategy. All of this suggests that ZCCHC17 is integral for normal neuronal functioning. However, the proteomic and electrophysiologic consequences of ZCCHC17 knockdown have not previously been explored in neurons.

In Cortese et al., recently published in the Journal of Neuropathology & Experimental Neurology, we evaluate the functional consequences of reduced ZCCHC17 expression in primary cortical cultures. Consistent with ZCCHC17’s predicted role as a master regulator of synaptic genes, we find that ZCCHC17 knockdown leads to a loss of synaptic protein expression using a range of markers. Patch recording of neurons shows that loss of ZCCHC17 significantly disrupts the E/I balance of neurotransmission and favors excitatory-dominant synaptic activity, as measured by an increase in spontaneous excitatory post synaptic currents (sEPSCs) and action potential firing rate and a decrease in spontaneous inhibitory post synaptic currents (sIPSCs). We are the first to assess the functional consequences of reduced ZCCHC17 expression in neurons, and conclude that ZCCHC17 is necessary to maintain synaptic protein expression and proper E/I balance of neurotransmission, and that loss of ZCCHC17 function may contribute to hyperexcitability in AD.

Andrew F. Teich, MD, PhD
Associate Professor of Pathology and Cell Biology (in Neurology)
aft25@cumc.columbia.edu