Dimerization of the Alzheimer's disease pathogenic receptor SORLA regulates its association with retromer

Mutations in the SORL1 gene confer exceptionally high risk of Alzheimer's disease (AD)—on par with the risk associated with mutations in APPPSEN1, and PSEN2—bringing it into the top 4 of genes considered causal of AD. SORLA, encoded by the SORL1 gene, is a sorting receptor acting together with the protein complex retromer to ensure endosomal recycling of cell-surface proteins, of great importance in maintaining neuronal integrity and function by guiding various neuroreceptors to synaptic membranes. It is important to understand the role of SORLA in this trafficking pathway and how this relates to AD. Here, we show that SORLA dimerizes and that the mode of dimerization reinforces retromer assembly and function, presenting strategies for AD therapeutics.