Cellular hormetic response to 27-hydroxycholesterol promotes neuroprotection through AICD induction of MAST4 abundance and kinase activity

Brendan Gongol, Traci L. Marin, John D. Jeppson, Karina Mayagoitia, Samuel Shin, Nicholas Sanchez, Wolff M. Kirsch, Harry V. Vinters, Christopher G. Wilson, Othman Ghribi, Salvador Soriano

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3 Scopus citations

Abstract

The function of the amyloid precursor protein (APP) in brain health remains unclear. This study elucidated a novel cytoprotective signaling pathway initiated by the APP transcriptionally active intracellular domain (AICD) in response to 27-hydroxycholesterol (27OHC), an oxidized cholesterol metabolite associated with neurodegeneration. The cellular response to 27OHC was hormetic, such that low, but not high, doses promoted AICD transactivation of microtubule associated serine/threonine kinase family member 4 (MAST4). MAST4 in turn phosphorylated and inhibited FOXO1-dependent transcriptional repression of rhotekin 2 (RTKN2), an oxysterol stress responder, to optimize cell survival. A palmitate-rich diet, which increases serum 27OHC, or APP ablation, abrogated this response in vivo. Further, this pathway was downregulated in human Alzheimer's Disease (AD) brains but not in frontotemporal dementia brains. These results unveil MAST4 as functional kinase of FOXO1 in a 27OHC AICD-driven, hormetic pathway providing insight for therapeutic approaches against cholesterol associated neuronal disorders.

Original languageEnglish (US)
Article number13898
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

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    Gongol, B., Marin, T. L., Jeppson, J. D., Mayagoitia, K., Shin, S., Sanchez, N., Kirsch, W. M., Vinters, H. V., Wilson, C. G., Ghribi, O., & Soriano, S. (2017). Cellular hormetic response to 27-hydroxycholesterol promotes neuroprotection through AICD induction of MAST4 abundance and kinase activity. Scientific reports, 7(1), [13898]. https://doi.org/10.1038/s41598-017-13933-9