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Dual‐specificity phosphatase 26 ( DUSP 26) stimulates Aβ42 generation by promoting amyloid precursor protein axonal transport during hypoxia
Author(s) -
Jung Sunmin,
Nah Jihoon,
Han Jonghee,
Choi SeonGuk,
Kim Hyunjoo,
Park Jaesang,
Pyo HaKyung,
Jung YongKeun
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13597
Subject(s) - phosphatase , amyloid precursor protein secretase , amyloid precursor protein , microbiology and biotechnology , kinase , regulator , chemistry , dual specificity phosphatase , biology , phosphorylation , biochemistry , alzheimer's disease , medicine , gene , disease
Abstract Amyloid beta peptide (Aβ) is a pathological hallmark of Alzheimer's disease ( AD ) and is generated through the sequential cleavage of amyloid precursor protein ( APP ) by β‐ and γ‐secretases. Hypoxia is a known risk factor for AD and stimulates Aβ generation by γ‐secretase; however, the underlying mechanisms remain unclear. In this study, we showed that dual‐specificity phosphatase 26 ( DUSP 26) regulates Aβ generation through changes in subcellular localization of the γ‐secretase complex and its substrate C99 under hypoxic conditions. DUSP 26 was identified as a novel γ‐secretase regulator from a genome‐wide functional screen using a cDNA expression library. The phosphatase activity of DUSP 26 was required for the increase in Aβ42 generation through γ‐secretase, but this regulation did not affect the amount of the γ‐secretase complex. Interestingly, DUSP 26 induced the accumulation of C99 in the axons by stimulating anterograde transport of C99‐positive vesicles. Additionally, DUSP 26 induced c‐Jun N‐terminal kinase ( JNK ) activation for APP processing and axonal transport of C99. Under hypoxic conditions, DUSP 26 expression levels were elevated together with JNK activation, and treatment with JNK inhibitor SP 600125, or the DUSP 26 inhibitor NSC ‐87877, reduced hypoxia‐induced Aβ generation by diminishing vesicle trafficking of C99 to the axons. Finally, we observed enhanced DUSP 26 expression and JNK activation in the hippocampus of AD patients. Our results suggest that DUSP 26 mediates hypoxia‐induced Aβ generation through JNK activation, revealing a new regulator of γ‐secretase‐mediated APP processing under hypoxic conditions.We propose the role of phosphatase dual‐specificity phosphatase 26 (DUSP26) in the selective regulation of Aβ42 production in neuronal cells under hypoxic stress. Induction of DUSP26 causes JNK‐dependent shift in the subcellular localization of γ‐secretase and C99 from the cell body to axons for Aβ42 generation. These findings provide a new strategy for developing new therapeutic targets to arrest AD progression.