A transcriptional mechanism for retromer misregulation

Abstract

AbstractBackgroundTranscription factors (TFs) regulate gene expression and define cellular homeostasis. This occurs via poorly resolved combinations of TFs that synergistically coordinate transcriptional decisions (Lambert et al., 2018). TFs are also drivers of pathology (Lee and Young, 2013), as aberrant transcriptional changes commonly develop in disease states. Recent transcriptomic profiles of the Alzheimer’s disease (AD) brain indicate that specific groups of genes become deregulated during the course of disease progression (Mathys et al., 2019; Small et al., 2005; Zhang et al., 2013), highlighting the need to understand how TF‐mediated mechanisms of gene expression fail during AD pathogenesis.MethodCellular models of disease counterpointed with analyses of AD postmortem tissue that employed a combination of DNA‐, RNA‐, and protein‐based approaches.ResultWe report the characterization of a transcription factor heterodimer linked to Alzheimer’s disease (AD). This complex is enriched in the dorsolateral prefrontal cortex of late‐onset AD patients and functions as a sensor of β‐amyloid stimuli in neurons. We additionally identify the retromer, a master orchestrator of endosome sorting and amyloid precursor protein metabolism (Small and Petsko, 2015), as an AD‐relevant transcriptional target of this heterodimer, and connect its accumulation in AD to disrupted retromer gene expression.ConclusionOur findings support a mechanism of retromer dysfunction promoted by an AD‐associated transcriptional pathway. Conceptually, they also argue for the importance of probing TF interactions as a way to understand gene expression, both in normalcy and during disease pathogenesis.