Oncotarget

Research Papers: Gerotarget (Focus on Aging):

E3 ligase mahogunin (MGRN1) influences amyloid precursor protein maturation and secretion

Stefano Benvegnù, Tina Wahle and Carlos G. Dotti _

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Oncotarget. 2017; 8:89439-89450. https://doi.org/10.18632/oncotarget.20143

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Abstract

Stefano Benvegnù1, Tina Wahle2 and Carlos G. Dotti1

1 Department of Molecular Neurobiology, Centro de Biología Molecular ”Severo Ochoa”, CSIC-UAM, Madrid, Spain

2 IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany

Correspondence to:

Carlos G. Dotti, email:

Stefano Benvegnù, email:

Keywords: Alzheimer’s disease, APP, amyloid beta, mahogunin, trafficking, Gerotarget

Received: May 13, 2017 Accepted: July 26, 2017 Published: August 10, 2017

Abstract

Altered processing of the Amyloid Precursor Protein (APP) is a well-recognized central pathogenic mechanism in Alzheimer’s Disease (AD), and regulation of APP processing is a major focus of research in the AD field. However, how age-associated cellular and molecular changes contribute to changes in the amyloidogenic processing of APP have not been extensively clarified so far. We here provide evidence that the processing of APP is influenced by the e3 ubiquitin ligase Mahogunin (MGRN1), a neuroprotective molecule whose levels decrease with aging. Specifically, the expression of MGRN1 inhibits the maturation of APP by sequestering it in the secretory pathway. This sequestration significantly delayed the proteolytic processing of APP, resulting in a reduced β-amyloid (Aβ) peptide release into the extracellular environment. Accordingly, a reduction of MGRN1 levels in hippocampal neurons, as it occurs during physiological aging, leads to an increased Aβ40 and Aβ42 release. We therefore propose that age contributes to the amyloidogenic processing of APP by altering its intracellular trafficking along the secretory pathway due in part to the down-regulation of MGRN1.


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