Mechanism of ZCCHC6 Regulation of Mitochondrial Dysfunction In Alzheimer's Disease

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PROJECT SUMMARY Mitochondrial dysfunction is an early prominent feature in susceptible neurons in the brain of patients with Alzheimer's disease (AD), which likely plays a critical role in the pathogenesis of AD. Mitochondria are dynamic organelles that undergo continual fission and fusion events. Recent advances indicate that excessive mitochondrial division (fission) is associated with functional defects and is implicated in multiple human diseases including neurodegenerative diseases. Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurodegenerative diseases including AD. Increased production of reactive oxygen species (ROS) and disease-dependent loss of mitochondrial function are likely causally involved in loss of hippocampal neuronal function in AD. However, molecular mechanisms underlying oxidative stress-induced abnormal mitochondrial dynamics are yet to be determined. Mitochondrial dynamics and function may be modulated by dysregulation of factors associated with mitochondrial fission. The major executor of fission is the dynamin related protein 1 (DRP1), a mainly cytosolic protein which translocates to the mitochondrial surface in order to mediate fission. Mff and Mid49/51 are mitochondrial membrane proteins that recruit DRP1 to the mitochondria for fission. It is well established that expression of Mff and Mid49 are post-transcriptionally regulated by specific miRNAs but it is not known why this regulation fails resulting in the increased mitochondrial fission in AD. Importantly, our preliminary data demonstrated that in neuronal cells oxidative stress induce the expression of ZCCHC6 which has been shown by us, and others, to uridylate miRNAs rendering them ineffective in regulating gene expression. In our preliminary studies we also found mitochondrial network fragmentation in N2a neurons with induced oxidative stress and that genes that regulate mitochondrial fission (Mff, Mid49) were upregulated and miRNAs predicted to regulate their expression were downregulated. Therefore, our basic hypothesis is that “Oxidative stress induced Zcchc6 in neurons contributes to AD pathogenesis by rendering specific miRNAs that regulate mitochondrial fission factors ineffective by uridylation which enhance mitochondrial fission and that inhibiting ZCCHC6 has the potential to inhibit and/or reverse mitochondrial dysfunction in AD”. To test this hypothesis, we will characterize in detail the causal role of aberrant ZCCHC6 expression in mediating oxidative stress-induced mitochondrial fragmentation in neurons in vitro and the impact of in vivo depletion of Zcchc6 in two preclinical models on the development of AD and cognitive impairment. Our findings will allow us to understand the biological and clinical relevance of oxidative stress-induced upregulation of Zcchc6 and miRNA uridylation to regulate expression of signature genes associated with mitochondrial impairment and fission in AD. Therefore, the results of our study would likely have a major impact on AD research toward designing novel preventive and/or therapeutic strategies.