Accumulating evidence suggests that Alzheimer's Disease (AD) begins as a synaptic disorder. This view is supported by work showing that toxic levels of ?-amyloid protein are associated with synaptic dysfunction and memory loss long before atrophy and cell death occur. Inspired by this observation, I have used bioinformatics tools to search for causes of synaptic dysfunction in AD. I have identified a transcription factor called ZCCHC17 that is reduced in AD brain tissue, and my hypothesis is that low levels of this transcription factor contribute to synaptic dysfunction in AD. My hypothesis is supported by my preliminary data (see below). Based on its structure and nuclear localization, ZCCHC17 is predicted to regulate gene expression. However, it is not well studied, and has not previously been linked to AD. Further study of ZCCHC17's role in synaptic dysfunction in AD may provide a therapeutic strategy to rescue synaptic plasticity and memory in this disease. I arrived at my hypothesis using a combination of computational and wet-lab techniques. I began by using novel statistical techniques to screen RNA expression profiles from laser-dissected neurons taken from human AD and control brains. My goal was to identify transcription factors that: 1) Are predicted to regulate a large number of synaptic targets, and 2) Are predicted to have impaired function in AD. My strongest candidate from this work is ZCCHC17. I have now shown that 1) ZCCHC17 protein levels are decreased in AD brain homogenate, and 2) ZCCHC17 is primarily located in neuronal nuclei and is decreased in AD. Although compelling, this data is still only correlational. Since ZCCHC17 is not well studied, the goal of this proposal is to generate foundational data that supports my hypothesis that ZCCHC17 is important for synaptic function and is impaired in AD. This data will justify a more in-depth study of ZCCHC17 in a future project.
In Aim 1, I will test the hypothesis that ZCCHC17 is a transcription factor that regulates synaptic genes. I will do this first using ChIP-seq, which will allow me to determine if ZCCHC17 binds to DNA. If ZCCHC17 binds to DNA regulatory regions, then this supports the hypothesis that ZCCHC17 is a transcription factor that regulates gene expression. I will perform ChIP-seq in several different tissues in order to increase my understanding of ZCCHC17's role in neuronal function (human tissue, SY5Y cells, mouse hippocampal neurons, and adult mouse brain). I will also perform siRNA knock-down of ZCCHC17 in the last three tissues. If siRNA knock- down of ZCCHC17 causes reduced expression of ZCCHC17's predicted synaptic targets, then this supports the hypothesis that ZCCHC17 regulates the expression of these synaptic genes.
In Aim 2, I will test the hypothesis that elevated ?-amyloid levels lead to lower ZCCHC17 protein levels. I have preliminary data supporting this hypothesis, and I will directly test this hypothesis in SY5Y cells, mouse hippocampal neuronal cultures, and in adult mouse cortex. If this prediction is true, then this supports the hypothesis that ?-amyloid impairs ZCCHC17 function.

Public Health Relevance

I am investigating the role of a protein called ZCCHC17 in Alzheimer's disease. My hypothesis is that ZCCHC17 is important for normal brain functioning, and that decreased ZCCHC17 levels may lead to dementia in Alzheimer's disease. If we can better understand how reduced ZCCHC17 levels contribute to Alzheimer's disease, we may be able to prevent or slow dementia by restoring the function of this protein.

National Institute of Health (NIH)
Small Research Grants (R03)
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Special Emphasis Panel (ZAG1)
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Petanceska, Suzana
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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