ZCCHC17 IMPAIRMENT IS A SIGNIFICANT DRIVER OF NEURONAL DYSFUNCTION IN ALZHEIMER’S DISEASE

Abstract

Our laboratory is using bioinformatic tools to investigate potential master regulators of gene expression in cortical neurons that are disrupted in Alzheimer's disease (AD). This analysis has resulted in the identification of a protein (called ZCCHC17) which is ranked highly in our analysis in two important ways: 1) As a potential master regulator of gene expression generally, and 2) As a potential master regulator of synaptic genes specifically. Our analysis predicts that ZCCHC17 has impaired activity in AD, and that this impairment may partially explain dysregulation of synaptic gene expression in AD. Our goal is to experimentally test these predictions and investigate the mechanism of how this occurs. We have examined ZCCHC17 protein levels in human AD brain tissue and investigated its physiologic role in rodent cortical cultures and (more recently) in human iPS (induced pluripotent stem cell) neurons. We have determined that ZCCHC17 protein (I) Is localized to neuronal nuclei and nucleoli in the CNS, (II) Is decreased in Alzheimer's disease brain tissue, (III) Directly or Indirectly regulates gene expression of 60% of its predicted synaptic targets in rodent cortical cultures, and (IV) ZCCHC17 knock-down causes aberrations in both the potassium current and in calcium-mediated activity. Current work in our laboratory is focused on better understanding the normal physiologic role of ZCCHC17 and how this contributes to our understanding of neurodegeneration in AD. Our preliminary data suggest that ZCCHC17 may normally be responsible for mRNA splicing, and that this may be impaired when ZCCHC17 is dysfunctional. We are also investigating the localization of ZCCHC17 in the nucleus to identify proteins that ZCCHC17 may interact with. Finally, our preliminary data has linked possible drivers of AD pathology to ZCCHC17 dysfunction. Taken together, these data indicate that ZCCHC17 supports normal synaptic physiology, and further supports the hypothesis that ZCCHC17 impairment contributes to disease pathogenesis in AD.