UPR Induction Prevents Iron Accumulation and Oligodendrocyte Loss in ex vivo Cultured Hippocampal Slices.

Sinead Healy,Jill Mcmahon,Una Fitzgerald

doi:10.3389/fnins.2018.00969

Abstract

The accumulation of iron within the brain occurs in many chronic disorders including Alzheimer’s and Parkinson’s disease and multiple sclerosis. Outside the CNS, a link between levels of iron and the unfolded protein response has already been established. To determine if such a relationship operates in within the brain, we used our ex vivo hippocampal slice-based model of iron accumulation. Ferrocene addition caused accumulation of iron within slices and loss of oligodendrocytes, an effect that was partially inhibited when ferrocene and ER stressor tunicamycin (Tm) were added together. An upward trend (not found to be statistically significant) in the expression of UPR transcripts in response to ferrocene was demonstrated using real-time PCR, while a significant upregulation of mRNA for B cell immunoglobulin-binding protein (BiP) and C/EBP homologous binding protein (CHOP) occurred following exposure to Tm. In silico analysis revealed consensus DNA-binding sequences for UPR-associated transcription factors within the promoter regions of eight iron-regulatory genes. In addition, dual-staining for CHOP and oligodendrocyte transcription factor 2 (OLIG2) or Ionized calcium binding adaptor molecule 1 (Iba1) showed nuclear expression of CHOP in some oligodendrocyte-lineage cells in response to Tm or Tm+ferrocene, but CHOP was rarely found in microglia. Co-expression of UPR-associated activated transcription factor 6 (ATF6) was detected in the nuclei of some oligodendrocyte-lineage cells exposed to Tm alone, or to Tm and ferrocene, but rarely in microglia. These data highlight the therapeutic potential of targeting UPR-associated proteins when developing novel treatments for chronic brain disorders that are affected by dysregulated iron.

Highlights

program activated upon disturbed homeostasis in the endoplasmic reticulum
infrequent hints have documented an interplay between the unfolded protein response (UPR) and iron metabolism
reports are few on the possible links between the UPR

Summary

Introduction

The unfolded protein response (UPR) is a ‘check and balance’ program activated upon disturbed homeostasis in the endoplasmic reticulum. Iron-UPR Cross-Talk in the Brain and iron within the brain (Liu and Connor, 2012; Rahman et al, 2017, 2018; Lumsden et al, 2018). A better understanding of this cross-talk might provide further clues regarding disease pathogenesis, given that aberrant iron metabolism and increased expression of markers of the UPR have been independently reported in several neurodegenerative diseases (Hetz and Mollereau, 2014), including multiple sclerosis (Stephenson et al, 2014), Alzheimer’s disease and Parkinson’s disease (Mercado et al, 2013; Ward et al, 2014). As a foundation for future studies, the overall goal of this work was to confirm and characterize the reciprocal relationship between UPR and iron homeostasis within our hippocampal slice-based model (Healy et al, 2016) of the accumulation of iron within the CNS

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Conclusion