The Potential Role of Protein Kinase R as a Regulator of Age-Related Neurodegeneration

Abstract

There is a growing evidence describing a decline in adaptive homeostasis in aging-related diseases affecting the central nervous system (CNS), many of which are characterized by the appearance of non-native protein aggregates. One signaling pathway that allows cell adaptation is the integrated stress response (ISR), which senses stress stimuli through four kinases. ISR activation promotes translational arrest through the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α) and the induction of a gene expression program to restore cellular homeostasis. However, depending on the stimulus, ISR can also induce cell death. One of the ISR sensors is the double-stranded RNA-dependent protein kinase [protein kinase R (PKR)], initially described as a viral infection sensor, and now a growing evidence supports a role for PKR on CNS physiology. PKR has been largely involved in the Alzheimer's disease (AD) pathological process. Here, we reviewed the antecedents supporting the role of PKR on the efficiency of synaptic transmission and cognition. Then, we review PKR's contribution to AD and discuss the possible participation of PKR as a player in the neurodegenerative process involved in aging-related pathologies affecting the CNS.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; aging; double-stranded RNA-dependent protein kinase; integrated stress response; neurocognitive functions.

FIGURE 1

Possible mechanistic links between the activation of the PKR-eIF2α branch of the ISR and hippocampal/cortical plasticity under physiological and age-related neurodegenerative conditions. The diagram represents the potential role of the double-stranded RNA protein kinase [protein kinase R (PKR)] in synaptic transmission efficiency under physiological conditions (left side) and age-related neurodegenerative conditions (right side). PKR-activating stimuli induce a significant increase in the phosphorylation (P) of the alpha subunit eukaryotic initiation factor 2 (eIF2α) in a dsRNA-dependent manner or via its endogenous activator RAX/PACT. This pathway activation promotes the inhibition of mRNA translation and ATF4 dependent gene reprogramming of several cellular functions. Altogether, PKR-eIF2α ISR branch activation may lead to cell adaptation or cell death. PKR-eIF2α ISR branch loss of function (LOF) under physiological conditions (left side) significantly modifies cortical and hippocampal receptor-mediated synaptic transmission. Consequently, long-term potentiation (LTP) and long-term depression (LTD) are also affected. Under age-related neurodegenerative conditions (right side), common stimuli could participate in the activation of PKR-eIF2α ISR branch activation in Huntington’s diseases (HD), Parkinson’s disease (PD), and Alzheimer’s disease (AD). Under this activation, ATF4 translocates to the nucleus and mediates degenerative reprogrammation. On the other hand, the eIF2α phosphorylation decreases mRNA translation. This decrease in translation induces modifications in the hippocampal and cortex LTP and LTD through an unknown mechanism.

FIGURE 2

The role of protein kinase R (PKR) in CNS physiology and pathophysiology. A schematic view of the modulation exerts by PKR in CNS morpho-functional integrity at different levels under physiological conditions and in Alzheimer’s (AD) disease. The information available for age-related neurodegenerative diseases is included.