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

Tina Wahle,Stefano Benvegnù,Carlos G Dotti

doi:10.18632/oncotarget.20143

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.

Highlights

The pathogenesis of Alzheimer’s disease (AD) is linked to the proteolytic processing of the amyloid precursor protein (APP) to the amyloidogenic peptide Aβ
We have recently demonstrated that MGRN1/Mahogunin decreases in old hippocampal neurons [9] and numerous works have stressed the importance of the neuronsendomembrane system in the amyloidogenic processing of APP [6,14]
We here described that another protein (i.e. MGRN1), whose levels change with aging, is associated to APP processing, and that the reduced MGRN1 levels observed with aging can influence APP metabolism towards a pro-amyloidogenic phenotype

Summary

INTRODUCTION

The pathogenesis of Alzheimer’s disease (AD) is linked to the proteolytic processing of the amyloid precursor protein (APP) to the amyloidogenic peptide Aβ. The amyloidogenic processing of APP occurs by sequential cleavage by β- and γ-secretase to release Aβ peptide. The complete molecular mechanism(s) and cellular compartment(s) involved in APP cleavage and Aβ production are still under debate [5]. Amyloidogenic processing mostly occurs following transition through the Golgi apparatus and in endosomal compartments, where acidic conditions favors optimal activity of β-secretase [6]. Factors that regulate APP trafficking and processing can, in turn, regulate Aβ production and release in the extracellular milieu. The identification of such factors is important to understand the pathogenesis of AD and its consequences. This moved us to investigate a potential MGRN1 function in the context of AD

RESULTS

DISCUSSION

MATERIALS AND METHODS