Cellular hormetic response to 27-hydroxycholesterol promotes neuroprotection through AICD induction of MAST4 abundance and kinase activity
| Autor: | Othman Ghribi, Salvador Soriano, Wolff M. Kirsch, John David Jeppson, Harry V. Vinters, Nicholas Sanchez, Brendan Gongol, Karina Mayagoitia, Samuel Shin, Traci L. Marin, Christopher G. Wilson |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Aging Transcription Genetic Intracellular Space lcsh:Medicine Neurodegenerative Alzheimer's Disease chemistry.chemical_compound Transactivation Mice Amyloid beta-Protein Precursor 0302 clinical medicine Amyloid precursor protein 2.1 Biological and endogenous factors Aetiology Phosphorylation lcsh:Science Multidisciplinary Tumor biology Kinase Forkhead Box Protein O1 Intracellular Signaling Peptides and Proteins Protein-Serine-Threonine Kinases Cell biology 27-Hydroxycholesterol Neurological Signal transduction Microtubule-Associated Proteins Transcription Oxysterol Protein Serine-Threonine Kinases Neuroprotection Article Cell Line 03 medical and health sciences Hormesis Genetic Alzheimer Disease Cell Line Tumor Acquired Cognitive Impairment Animals Humans Kinase activity lcsh:R Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Hydroxycholesterols Rats Brain Disorders 030104 developmental biology chemistry Gene Expression Regulation biology.protein lcsh:Q Dementia Protein Kinases 030217 neurology & neurosurgery |
| Zdroj: | Scientific reports, vol 7, iss 1 Scientific Reports, Vol 7, Iss 1, Pp 1-11 (2017) Scientific Reports |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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