College of Pharmacy
The overall goal of this project is to elucidate the role of protein prenylation, a key posttranslational lipid modification of proteins, in the pathogenesis of Alzheimer’s disease (AD). Protein prenylation is catalyzed by farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT) and -2. These enzymes attach short-chain lipid molecules called isoprenoids including farnesylpyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), to proteins that have CAAX motif at their C-terminus, facilitating the anchoring of the proteins to cell membranes and their proper functions. The superfamily of small GTPases, including Ras, Rho, and Rab superfamilies, is the most extensively studied group of proteins that undergo prenylation, which affect their intracellular trafficking, subcellular organization, and interactions with their downstream effectors. Small GTPases function as molecular switches in multiple signaling pathways and regulate a wide range of cellular processes. Emerging evidence indicates that protein prenylation plays an important role in the pathogenic process of AD. Studies in vitro studies and in animal models have demonstrated that modulation of isoprenoid production and protein prenylation using pharmacological or genetic approaches influences metabolism/deposition of Aβ and tau, synaptic plasticity, and cognitive function. However, only few small-scale genetic studies have been performed on protein prenylation-related pathways in the brains of clinically diagnosed AD patients. Moreover, the scope of dysregulation of protein prenylation among various substrate proteins in AD has not been thoroughly investigated.
MSI resources are required to to accomplish a sub-aim of the project, identifying associations between genetic changes of genes pertinent to protein prenylation or prenylated proteins and AD pathology. In preliminary studies using immunoblot assay in postmortem human brain samples from the ROS cohort, the researchers found that prenylated H-Ras/Rac1/Cdc42 were elevated in brains from both mild cognitive impairment (MCI) and AD groups, suggesting upregulation of prenylation in the early stage of AD pathogenesis. This increase in prenylated form of selected proteins were accompanied by the elevation of FT an GGT. However, studying a wide range of small GTPases prenylation in AD using immunoblot assay is challenging, and targeted pathway analysis is limited by the availability of validated antibodies. Therefore, to further investigate the relationship between prenylation and AD throughout the disease progression in a systemic manner, the researchers plan to perform differential gene expression analysis on target genes that are involved in isoprenoid synthesis, protein prenylation and small GTPases signal transduction pathways using the ROSMAP bulk RNA-Seq database. Any identified differentially expressed genes will be correlated with patients’ cognitive diagnosis and pathology measures such as plaques, tangles, and cerebral amyloid angiopathy to further dissect the role of prenylation in the pathogenic process of AD. This approach will allow the group not only to evaluate the overall changes in prenylation dynamics, but to identify AD pathology-associated downstream signaling pathways which then can be exploited for therapeutic development.