ArticleScientific reports2017
Cellular hormetic response to 27-hydroxycholesterol promotes neuroprotection through AICD induction of MAST4 abundance and kinase activity.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
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- MAST4 regulates stem cell maintenance with DLX3 for epithelial development and amelogenesis.Experimental & molecular medicine · 2024Article
- Nuclear MAST4 Suppresses FOXO3 through Interaction with AKT3 and Induces Chemoresistance in Pancreatic Ductal Carcinoma.International journal of molecular sciences · 2024Article
- Identification of novel candidate genes associated with non-syndromic tooth agenesis in Mongolian families.Clinical oral investigations · 2023Article
- MAST4 promotes primary ciliary resorption through phosphorylation of Tctex-1.Life science alliance · 2023Article
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- From bugs to bedside: functional annotation of human genetic variation for neurological disorders using invertebrate models.Human molecular genetics · 2022Article
- Loss of APP in mice increases thigmotaxis and is associated with elevated brain expression of IL-13 and IP-10/CXCL10.Physiology & behavior · 2021Article
- Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation.International journal of molecular sciences · 2020Article
- Detecting the Multiomics Signatures of Factor-Specific Inflammatory Effects on Airway Smooth Muscles.Frontiers in genetics · 2020Article
- Loss of amyloid precursor protein exacerbates early inflammation in Niemann-Pick disease type C.Journal of neuroinflammation · 2019Article
- 27-hydroxycholesterol promotes Aβ accumulation via altering Aβ metabolism in mild cognitive impairment patients and APP/PS1 mice.Brain pathology (Zurich, Switzerland) · 2019Article
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Authors and funding
11 authors at 3 institutions in 1 country.
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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.
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