RhoGEF12 regulates endosomal SORL1-retromer and its inhibition is therapeutic in human neuronal models of Alzheimer's disease.
Article
Overview
abstract
The interaction of the endosomal sorting protein SORL1 with the retromer complex at endosomal membranes controls a recycling pathway whose dysfunction is pathogenic in Alzheimer's disease (AD) and is linked to other neurodegenerative disorders. To search for novel therapeutic targets, we hypothesize that endosomal SORL1-retromer might be regulated by SORL1's cytoplasmic tail. We begin by completing an in vitro analysis of the tail and show that its phosphorylation by ROCK2 (Rho-associated kinase 2) reduces SORL1's affinity to retromer. Since RhoGEF12 (Rho guanine nucleotide exchange factor 12) is an upstream activator of ROCK2 that is upregulated in AD, we used a RhoGEF12 pharmacological inhibitor to mechanistically and therapeutically validate the findings in neuronal cultures. First, in mouse neurons we confirm that the inhibitor increases endosomal SORL1-retromer. Next, we turned to human iPSC-derived neurons to show that the inhibitor reduces Aβ40 and Aβ42, an indicator of pathway upregulation, in a SORL1-dependent manner. Finally, we validate its therapeutic potential by applying the RhoGEF12 inhibitor to human iPSC-derived neurons expressing AD-associated mutations in either APP or SORL1. Collectively, our results identify a novel and therapeutically amenable mechanism that regulates endosomal SORL1-retromer and preclinically validate RhoGEF12 as a therapeutic target for AD and potentially other neurodegenerative disorders.
