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A transcriptional mechanism for retromer misregulation
Author(s) -
Roque Cláudio Gouveia,
Baleriola Jimena,
Hengst Ulrich
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.043880
Subject(s) - retromer , endosome , biology , transcription factor , transcriptome , amyloid precursor protein , gene , microbiology and biotechnology , transcriptional regulation , gene expression , presenilin , disease , alzheimer's disease , neuroscience , genetics , medicine , intracellular , pathology
Background Transcription 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. Method Cellular models of disease counterpointed with analyses of AD postmortem tissue that employed a combination of DNA‐, RNA‐, and protein‐based approaches. Result We 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. Conclusion Our 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.