A Role for PREPL in Protein Trafficking and Endocytosis, with Implications in Alzheimer’s Disease

Prolyl endopeptidase-like protein (PREPL) is a putative oligopeptidase with a notable sequence homology with prolyl endopeptidase. Although the precise PREPL functions are unknown, PREPL is identified as one of the most downregulated proteins in Alzheimer’s Disease. As PREPL interacts with cytoskeletal and adaptor proteins, it is hypothesized to play a role in protein processing and trafficking pathways. My thesis aims to investigate how PREPL knockdown affects protein processing and intracellular transport, which may ultimately contribute to AD pathogenesis. Using mouse neuroblastoma and hippocampal cell models, we found PREPL knockdown decreases cell proliferation and reduces expressions of proteins related to the secretory pathway. Our proteomic analysis indicated a decreased level of proteins in the secretory pathway and an increased expression of mitochondrial proteins related to lipid metabolism. Using G-protein coupled receptor internalization assay, PREPL knockdown was demonstrated to attenuate agonist-induced receptor endocytosis. As a potential mechanism of PREPL function, protein palmitoylation was examined in control and PREPL knockdown condition. The results from palmitoylation assay shed light on the potential involvement of PREPL in protein lipidation and trafficking. Overall, our study suggests PREPL as a novel player in protein processing and trafficking, a critical pathway underlying the AD pathogenesis