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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Virology. Aug 12, 2015; 4(3): 188-197
Published online Aug 12, 2015. doi: 10.5501/wjv.v4.i3.188
Prion-induced neurotoxicity: Possible role for cell cycle activity and DNA damage response
Raymond Bujdoso, Matthias Landgraf, Walker S Jackson, Alana M Thackray
Raymond Bujdoso, Alana M Thackray, Department of Veterinary Medicine, University of Cambridge, CB3 0ES Cambridge, United Kingdom
Matthias Landgraf, Department of Zoology, University of Cambridge, CB2 3EJ Cambridge, United Kingdom
Walker S Jackson, German Center for Neurodegenerative Disease (DZNE), BMZ1, D-53127 Bonn, Germany
Author contributions: All authors contributed to this manuscript.
Supported by The NC3Rs, No. NC/K000462/1 (in part).
Conflict-of-interest statement: The authors declare that there are no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Raymond Bujdoso, Department of Veterinary Medicine, University of Cambridge, Madingley Road, CB3 0ES Cambridge, United Kingdom. rb202@cam.ac.uk
Telephone: +44-1223-337655 Fax: +44-1223-337610
Received: December 24, 2014
Peer-review started: December 26, 2014
First decision: February 7, 2015
Revised: April 8, 2015
Accepted: April 28, 2015
Article in press: April 30, 2015
Published online: August 12, 2015
Processing time: 232 Days and 10.1 Hours
Abstract

Protein misfolding neurodegenerative diseases arise through neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, motor neuron disease, tauopathies and prion diseases. Collectively, these conditions are a challenge to society because of the increasing aged population and through the real threat to human food security by animal prion diseases. It is therefore important to understand the cellular and molecular mechanisms that underlie protein misfolding-induced neurotoxicity as this will form the basis for designing strategies to alleviate their burden. Prion diseases are an important paradigm for neurodegenerative conditions in general since several of these maladies have now been shown to display prion-like phenomena. Increasingly, cell cycle activity and the DNA damage response are recognised as cellular events that participate in the neurotoxic process of various neurodegenerative diseases, and their associated animal models, which suggests they are truly involved in the pathogenic process and are not merely epiphenomena. Here we review the role of cell cycle activity and the DNA damage response in neurodegeneration associated with protein misfolding diseases, and suggest that these events contribute towards prion-induced neurotoxicity. In doing so, we highlight PrP transgenic Drosophila as a tractable model for the genetic analysis of transmissible mammalian prion disease.

Keywords: Neurodegenerative disease; Protein misfolding; Prion; Transmissible; Cell cycle; DNA repair; Chromatin; PrP transgenic Drosophila

Core tip: It is important to understand the cellular and molecular mechanisms of protein misfolding-induced neurotoxicity in order to combat conditions such as Alzheimer’s, Huntington’s, Parkinson’s, and motor neuron disease, tauopathies and prion diseases. Here, we review the role of cell cycle activity and the DNA damage response in neurodegeneration associated with protein misfolding diseases, including prion diseases. In doing so, we highlight PrP transgenic Drosophila as a tractable model of transmissible mammalian prion disease. Our review provides a new impetus to the study of prion diseases, which are increasingly seen as an important paradigm for neurodegenerative conditions in general.