Research Paper Volume 11, Issue 16 pp 6134—6152
Beta-amyloid induces apoptosis of neuronal cells by inhibition of the Arg/N-end rule pathway proteolytic activity
- 1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
- 2 Department of Biology, Texas Woman’s University, Denton, TX 76204, USA
- 3 Institute of Biology, Komi Science Center, Russian Academy of Sciences, Syktyvkar 167000, Russia
- 4 Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region 141701, Russia
- 5 Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow 121205, Russia
Received: April 22, 2019 Accepted: August 9, 2019 Published: August 24, 2019
https://doi.org/10.18632/aging.102177How to Cite
Copyright © 2019 Kechko et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY 3.0) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Alzheimer’s disease (AD) is accompanied by the dysfunction of intracellular protein homeostasis systems, in particular the ubiquitin-proteasome system (UPS). Beta-amyloid peptide (Aβ), which is involved in the processes of neurodegeneration in AD, is a substrate of this system, however its effect on UPS activity is still poorly explored. Here we found that Aβ peptides inhibited the proteolytic activity of the antiapoptotic Arg/N-end rule pathway that is a part of UPS. We identified arginyltransferase Ate1 as a specific component of the Arg/N-end rule pathway targeted by Aβs. Aβ bearing the familial English H6R mutation, known to cause early-onset AD, had an even greater inhibitory effect on protein degradation through the Arg/N-end rule pathway than intact Aβ. This effect was associated with a significant decrease in Ate1-1 and Ate1-3 catalytic activity. We also found that the loss of Ate1 in neuroblastoma Neuro-2a cells eliminated the apoptosis-inducing effects of Aβ peptides. Together, our results show that the apoptotic effect of Aβ peptides is linked to their impairment of Ate1 catalytic activity leading to suppression of the Arg/N-end rule pathway proteolytic activity and ultimately cell death.