Retromer Dysfunction and Neurodegenerative Disease

In recent years, genomic, animal and cell biology studies have implicated deficiencies in retromer-mediated trafficking of proteins in an increasing number of neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's Disease (PD) and Frontotemporal Lobar Degeneration (FTLD). The retromer complex, which is highly conserved across all eukaryotes, regulates the sorting of transmembrane proteins out of endosomes to the cell surface or to the trans-Golgi network. Within retromer, cargo selection and binding are performed by a trimer of the Vps26, Vps29 and Vps35 proteins, named the “Cargo-Selective Complex (CSC)”. Sorting of cargo into tubules for distribution to the trans-Golgi network or the cell surface is achieved through the dimeric sorting nexin (SNX) component of retromer and accessory proteins such as the WASH complex which mediates the formation of discrete endosomal tubules enabling the sorting of cargo into distinct pathways through production of filamentous actin patches. In the present article, we review the molecular structure and function of the retromer and summarize the evidence linking retromer dysfunction to neurodegenerative disease.