Hypoxia-Induced MicroRNA-210 Targets Neurodegenerative Pathways.

Michelle Watts,Jess Nithianantharajah,Charles Claudianos,Sarah Williams

doi:10.3390/ncrna4020010

Abstract

Hypoxia-regulated microRNA-210 (miR-210) is a highly conserved microRNA, known to regulate various processes under hypoxic conditions. Previously we found that miR-210 is also involved in honeybee learning and memory, raising the questions of how neural activity may induce hypoxia-regulated genes and how miR-210 may regulate plasticity in more complex mammalian systems. Using a pull-down approach, we identified 620 unique target genes of miR-210 in humans, among which there was a significant enrichment of age-related neurodegenerative pathways, including Huntington’s, Alzheimer’s, and Parkinson’s diseases. We have also validated that miR-210 directly regulates various identified target genes of interest involved with neuronal plasticity, neurodegenerative diseases, and miR-210-associated cancers. This data suggests a potentially novel mechanism for how metabolic changes may couple plasticity to neuronal activity through hypoxia-regulated genes such as miR-210.

Highlights

In recent years, increasing evidence has established microRNAs as critical regulators of neuronal development and plasticity, with new roles for neuronal miRNAs continually emerging
Isolation of messenger RNAs (mRNAs) targets was performed using a biotin pull-down technique first described by Orom et al and more recently modified to efficiently detect translationally regulated miRNA targets [22,23]. miRNA mimics were designed and synthesized as sense-strand miRNA oligo sequences using 2 O-methyl modified RNA bases that are less sensitive to degradation
Dysregulation of miR-210 itself has been correlated with Alzheimer’s disease (AD) being downregulated in brain samples within the anterior temporal cortex, frontal cortex, and hippocampal regions as well as in cerebrospinal fluid and serum of AD patients [44,45,46]. This data indicates that miR-210 may have a role in neurodegenerative disorders and supports a potentially significant neuronal function of miR-210. Within this gene set we looked at overrepresented transcription factor binding sites (TFBSs) using the oPOSSUM single site analysis tool (Table S5) [47]. miR-210 already has a well-established role in the regulation of hypoxia, being induced under hypoxic conditions through the hypoxia-inducible factor (HIF) TFBS in its promoter

Summary

Introduction

In recent years, increasing evidence has established microRNAs (miRNA) as critical regulators of neuronal development and plasticity, with new roles for neuronal miRNAs continually emerging. Rapid turnover of miRNAs has been identified by various activity-dependent mechanisms, including activation of the miRNA processing enzyme Dicer, calpain-mediated cleavage from the post-synaptic density (PSD), and activity-induced local degradation of RNA-induced silencing complex (RISC) proteins [3]. We examined changes in gene expression following long-term memory formation using olfactory conditioning in the honeybee [6]. This identified a broad downregulation of protein-coding genes and a corresponding upregulation of noncoding RNA genes. MiRNA-210 (miR-210) exhibited the highest upregulation following olfactory conditioning and was expressed in relevant learning-related regions of the honeybee brain. Knockdown of miR-210 in the honeybee revealed impairments in long-term recall following olfactory conditioning, providing the first evidence that miR-210 may be involved in learning and memory

Methods

Results

Conclusion