Prion-induced neurotoxicity: Possible role for cell cycle activity and DNA damage response

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.