Abstract
Our understanding of the highly specialized functions for small non-coding single-stranded RNA (ssRNA) in the transcriptome of the human central nervous system (CNS) continues to evolve. Circular RNAs (circRNAs), a recently discovered class of ssRNA enriched in the brain and retina, are extremely stable and intrinsically resilient to degradation by exonuclease. Conventional methods of ssRNA, microRNA (miRNA), or messenger RNA (mRNA) detection and quantitation requiring free ribonucleotide ends may have considerably underestimated the quantity and significance of CNS circRNA in the CNS. Highly-specific small ssRNAs, such as the ~23 nucleotide (nt) Homo sapien microRNA-7 (hsa-miRNA-7; chr 9q21.32), are not only abundant in the human limbic system but are, in addition, associated with a ~1400 nt circRNA for miRNA-7 (ciRS-7) in the same anatomical region. Structurally, ciRS-7 contains about ~70 tandem anti-miRNA-7 sequences and acts as an endogenous, anti-complementary miRNA-7 “sponge” that attracts, binds, and, hence, quenches, natural miRNA-7 functions. Using a combination of DNA and miRNA array technologies, enhanced LED-Northern and Western blot hybridization, and the magnesium-dependent exoribonuclease and circRNA-sensitive probe RNaseR, here we provide evidence of a significantly misregulated ciRS-7-miRNA-7-UBE2A circuit in sporadic Alzheimer’s disease (AD) neocortex (Brodmann A22) and hippocampal CA1. Deficits in ciRS-7-mediated “sponging events”, resulting in excess ambient miRNA-7 appear to drive the selective down-regulation in the expression of miRNA-7-sensitive mRNA targets, such as that encoding the ubiquitin conjugating enzyme E2A (UBE2A; chr Xq24). UBE2A, which normally serves as a central effector in the ubiquitin-26S proteasome system, coordinates the clearance of amyloid peptides via proteolysis, is known to be depleted in sporadic AD brain and, hence, contributes to amyloid accumulation and the formation of senile plaque deposits. Dysfunction of circRNA-miRNA-mRNA regulatory systems appears to represent another important layer of epigenetic control over pathogenic gene expression programs in the human CNS that are targeted by the sporadic AD process.
Highlights
In eukaryotic cells the post-translational modification of end-stage proteins with ubiquitin is an important cellular regulatory mechanism for the targeting and shuttling of abnormal, short-lived proteins, transcription factors, and/or neurotoxic proteins destined for degradation and proteolysis into the ubiquitin-26S proteasome system [1,2,3]
Dysfunction of circRNA-miRNA-messenger RNA (mRNA) regulatory systems appears to represent another important layer of epigenetic control over pathogenic gene expression programs in the human central nervous system (CNS) that are targeted by the sporadic Alzheimer’s disease (AD) process
Using a miRNA-array approach we quantified a significant increase in miRNA-7, miRNA-146a, and miRNA-155 in AD over an unchanging miRNA-183 or 5S RNA in the same sample analyzed; in this study ambient miRNA-7 was found to be increased to a mean of about three-fold over age-matched controls (p < 0.001, ANOVA; Figure 2A,B)
Summary
In eukaryotic cells the post-translational modification of end-stage proteins with ubiquitin is an important cellular regulatory mechanism for the targeting and shuttling of abnormal, short-lived proteins, transcription factors, and/or neurotoxic proteins destined for degradation and proteolysis into the ubiquitin-26S proteasome system [1,2,3]. Ubiquitin-mediated tagging, trafficking, and elimination of “waste” proteins plays a crucial role in cell-cycle regulation, DNA repair, cell growth, vesicular transport and immune function, and dysfunction of the ubiquitin-26S proteasome pathway is known to contribute to cancer, and immunological and neurodegenerative disorders [2,3,4,5,6,7]. A ubiquitin-activating enzyme UBE1, a ubiquitin-conjugating enzyme UBE2A, and a ubiquitin-protein ligase UBE3 [3,4,5,6]. The ubiquitin conjugating enzyme E2A (UBE2A) is part of an UBE2 enzyme group that catalyzes the transfer of ubiquitin from UBE1 to the active site cysteine of the UBE2A via a trans-thioesterification reaction and occupies a central regulatory position in the ubiquitination mechanism [3,4,5,6]. UBE2A (encoded at chr Xq24) is associated with neurological diseases that involve cognitive disruption, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), mental retardation, X-linked syndrome, X-linked intellectual disability (Nascimento type), and other progressive, age-related neurodegenerative disorders [2,3,4,5,6].
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