Abstract
Prion diseases are neurodegenerative pathologies characterized by the accumulation of a protease-resistant form of the cellular prion protein named prion protein scrapie (PrPSc) in the brain. PrPSc accumulation in the endoplasmic reticulum (ER) result in a dysregulated calcium (Ca2+) homeostasis and subsequent initiation of unfolded protein response (UPR) leading to neuronal dysfunction and apoptosis. The molecular mechanisms for the transition between adaptation to ER stress and ER stress-induced apoptosis are still unclear. Mitogen-activated protein kinases (MAPKs) are serine/threonine protein kinases that rule the signaling of many extracellular stimuli from plasma membrane to the nucleus. However the identification of numerous points of cross talk between the UPR and MAPK signaling pathways may contribute to our understanding of the consequences of ER stress in prion diseases. Indeed the MAPK signaling network is known to regulate cell cycle progression and cell survival or death responses following a variety of stresses including misfolded protein response stress. In this article, we review the UPR signaling in prion diseases and discuss the triad of MAPK signaling pathways. We also describe the role played by MAPK signaling cascades in Alzheimer’s (AD) and Parkinson’s disease (PD). We will also overview the mechanisms of cell death and the role of MAPK signaling in prion disease progression and highlight potential avenues for therapeutic intervention.
Highlights
The transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative disorders affecting both humans and animals
There are many evidences suggesting the role of misfolded prion proteins in the initiation of endoplasmic reticulum (ER) stress mediated inositol requiring enzyme 1 (IRE1), PERK and activating transcription factor 6 (ATF6) pathways
The adaptive response to ER stress is called unfolded protein response (UPR) which is aimed at correcting overall protein processing in order to reduce the accumulation of misfolded proteins and restore the normal cellular functions
Summary
The transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative disorders affecting both humans and animals. TSEs are associated with the accumulation and aggregation of misfolded/unfolded diseasespecific proteins in the brain leading to neuroinflammation and neurodegeneration. The exact molecular mechanisms leading to neurodegeneration in protein misfolding disorders including prion disease are still unclear. Prion disease model employing SH-SY5Y cell line infected with PrP106–126 have shown apoptotic signaling mediated by p38 MAPK pathway (Thellung et al, 2002). Wang et al (2005) have shown that p38 MAPK signaling cascade play a vital role in the induction of PrPc in N2a cell line. All major protein misfolding diseases, including AD, PD, Huntington’s disease (HD) and prion diseases have harmful effects on humans and animals due to lack of effective therapeutic strategies and presymptomatic diagnostic tools. In this review article, we will focus on the role of UPR and MAPK signaling cascades in neurodegenerative diseases with special focus on prion diseases
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