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Mediator is a transducer of amyloid-precursor-protein-dependent nuclear signalling.

ABSTRACT: Regulated intramembrane proteolysis of the amyloid precursor-protein (APP) produces both a characterstic amyloid-β peptide that contributes to neuritic plaque formation and neurodegeneration in Alzheimer disease and a small APP intracellular domain (AICD) that transcriptionally activates genes implicated in Alzheimer disease pathology. Although the biochemical events leading to amyloidogenic APP processing at the cell membrane have been described in detail, comparably little is known about the mechanistic basis of AICD-dependent gene regulation in the nucleus. In this study, we show that the AICD activates transcription by targeting MED12, an RNA polymerase II transcriptional Mediator subunit that is implicated in human cognitive development. The AICD binds to MED12/Mediator in vitro and in vivo. Disruption of the AICD/MED12 interaction inhibits AICD transactivation potential and expression of AICD target genes. Mediator, in a MED12-dependent manner, occupies only AICD-bound promoter DNA, indicating that the AICD recruits Mediator to activate transcription. These results identify the MED12 interface in Mediator as a crucial transducer of AICD transactivation and a potential therapeutic target in Alzheimer disease.

SUBMITTER: Xu X

PROVIDER: S-EPMC3059912 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:UnlabelledAmyloid precursor protein (APP) was originally identified as the source of β-amyloid peptides that accumulate in Alzheimer's disease (AD), but it also has been implicated in the control of multiple aspects of neuronal motility. APP belongs to an evolutionarily conserved family of transmembrane proteins that can interact with a variety of adapter and signaling molecules. Recently, we showed that both APP and its insect ortholog [APPL (APP-Like)] directly bind the heterotrimeric G-protein Goα, supporting the model that APP can function as an unconventional Goα-coupled receptor. We also adapted a well characterized assay of neuronal migration in the hawkmoth, Manduca sexta, to show that APPL-Goα signaling restricts ectopic growth within the developing nervous system, analogous to the role postulated for APP family proteins in controlling migration within the mammalian cortex. Using this assay, we have now identified Manduca Contactin (MsContactin) as an endogenous ligand for APPL, consistent with previous work showing that Contactins interact with APP family proteins in other systems. Using antisense-based knockdown protocols and fusion proteins targeting both proteins, we have shown that MsContactin is selectively expressed by glial cells that ensheath the migratory neurons (expressing APPL), and that MsContactin-APPL interactions normally prevent inappropriate migration and outgrowth. These results provide new evidence that Contactins can function as authentic ligands for APP family proteins that regulate APP-dependent responses in the developing nervous system. They also support the model that misregulated Contactin-APP interactions might provoke aberrant activation of Goα and its effectors, thereby contributing to the neurodegenerative sequelae that typify AD.Significance statementMembers of the amyloid precursor protein (APP) family participate in many aspects of neuronal development, but the ligands that normally activate APP signaling have remained controversial. This research provides new evidence that members of the Contactin family function as authentic ligands for APP and its orthologs, and that this evolutionarily conserved class of membrane-attached proteins regulates key aspects of APP-dependent migration and outgrowth in the embryonic nervous system. By defining the normal role of Contactin-APP signaling during development, these studies also provide the framework for investigating how the misregulation of Contactin-APP interactions might contribute to neuronal dysfunction in the context of both normal aging and neurodegenerative conditions, including Alzheimer's disease.

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Mediator is a transducer of amyloid-precursor-protein-dependent nuclear signalling.

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