Double-strand RNA dependent protein kinase (PKR) is involved in the extrastriatal degeneration in Parkinson's disease and Huntington's disease

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Abstract

Double-strand RNA dependent protein kinase (PKR) plays an important role in control of cell death. We previously reported that activation of PKR is associated with hippcampal neuronal loss in Alzheimer's disease (AD). Recent studies have reported that Parkinson's (PD) and Huntington's (HD) disease brains displayed progressive hippocampal neuronal loss in extrastriatal degeneration. However, association between PKR and hippocampal neuronal loss in PD and HD brains is not known. In this report, brain tissues from patients with PD and HD displayed strong induction of phosphorylated-PKR (p-PKR) in hippocampal neurons. Immunoblotting analysis also demonstrated that levels of nuclear p-PKR in the hippocampus affected by these diseases were increased compared with age-matched disease controls. These results suggest that a close association exists between PKR and extrastriatal degeneration in PD and HD pathology.

Introduction

Most clinical symptoms of Parkinson's disease (PD) and Huntington's disease (HD) have been attributed to either substantia nigra or striatal degeneration. However, previous studies have documented progressive hippocampal volume loss in PD and HD because postmortem studies demonstrated that almost all brain structures atrophy (Camicioli et al., 2003, Rosas et al., 2003). Furthermore, it is likely that at least some of the cognitive, behavioral and focal neurologic symptoms in PD and HD are due to degeneration of extrastriatal structures including hippocampus. Thus, extrastriatal degeneration may play an important role in clinical symptoms.

Recent findings suggest that ER stress appears to act at the early stage of the cell death process (Yu et al., 1999). Prolonged ER stress contributes to cell death (Kaufman, 1999, Bando et al., 2000, Bando et al., 2003), which is linked to pathogenesis of cerebrovascular disease (Bando et al., 2003, Miyazaki et al., 2002), Alzheimer's disease (AD) (Katayama et al., 1999, Manabe et al., 2003), and PD (Imai et al., 2002). Thus, ER stress is commonly associated with many neurodegenerative disorders.

We previously identified protein kinase (PKR) as an important molecule in ER stress using randomized-ribozyme mediated screening technology (Onuki et al., 2004, Kawasaki et al., 2002). PKR is an interferon-inducible, dsRNA-activated protein kinase that is ubiquitously expressed in all mammalian cells (Samuel et al., 1997, Donze et al., 2004). PKR plays an important role in antiviral defenses by interferon (Barachandran et al., 2000) and in NF-kB activation (Yang et al., 1995). PKR is involved in phosphorylation of the eukaryotic translation initiation factor 2 kinase (eEF2α, Williams, 1999, Kaufman, 1999). Furthermore, overexpression of PKR leads to apoptosis (Donze et al., 1999). In addition, recent findings suggest that PKR is involved in AD (Onuki et al., 2004, Peel and Bredesen, 2003, Suen et al., 2003, Chang et al., 2002), HD (Peel et al., 2001), amytrophic lateral sclerosis (Hu et al., 2003) and viral-induced encephalitis (Scheuner et al., 2003). These evidences indicate that PKR is implicated in extrastriatal degeneration via ER stress in PD and HD.

However, most studies concerning the role of PKR in neurodegenerative diseases have demonstrated that selective or restricted neuronal loss, such as hippocampal neuronal loss, is responsible for AD and neuronal loss in the substantia nigra is responsible for PD. Despite accumulating evidence regarding progressive hippocampal volume loss in PD and HD, the molecular mechanism of extrastriatal degeneration remains unknown.

The present investigation is intended to examine whether activation of PKR is involved in extrastriatal degeneration in PD and HD.

Section snippets

Immunohistochemistry

Prior to autopsies, we obtained consent from patients and their families to use samples for research only. Some human tissues were obtained from the Brain and Tissue Bank for Developmental Disorders at the University of Maryland (Baltimore, Maryland, USA). Autopsies of AD patients (four; mean age, 71.7 ± 4.3 y.o., mean duration, 11 years), of PD patients (three; mean age, 65 ± 4.3 y.o., mean duration, 19 years), of HD patients (two; 57 y.o., duration 27 years and 36 y.o., duration 5 years) and

Distribution of p-PKR in human brain

We first examined the autopsied hippocampus of age-matched disease control brains to clarify PKR expression. Immunohistochemical analysis revealed the expression of p-PKR in the hippocampal neurons in age-matched disease control brains (Fig. 1). Under high magnification, p-PKR was observed only in the cytoplasm of neurons in all regions (CA1, CA2 and CA3) of the hippocampus (Fig. 1B–D). As shown in Figure 5, positive neurons (localization of PKR in nuclei) accounted for only 2–6% of the total

Discussion

Even with a relatively small sample size, results of the present study indicated the implications of p-PKR in the extrastriatal degeneration in PD and HD brain. We propose a novel mechanism of the development of extrastriatal degeneration in PD and HD brains involving nuclear aggregation of p-PKR of the hippocampus.

Previous studies have demonstrated that PKR is involved in various neurodegenerative diseases (Suen et al., 2003, Peel et al., 2001, Hu et al., 2003, Scheuner et al., 2003). However,

Acknowledgements

This work was supported by Core Research for Evolutional Science, Japan Science and Technology (CREST, JST). The authors thank Dr. Alexey N. Aleshin (Osaka University) for helpful comments on the original manuscript.

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