Deficiency in the Ubiquitin Conjugating Enzyme UBE2A in Alzheimer’s Disease (AD) is Linked to Deficits in a Natural Circular miRNA-7 Sponge (circRNA; ciRS-7)

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.

Hsa_Circ_0001275: A Potential Novel Diagnostic Biomarker for Postmenopausal Osteoporosis

“…Owing to its closed loop structure, circRNA is not degraded by RNA exonuclease, making it highly conserved and remarkably stable. Therefore, circRNA can be a potential diagnostic biomarker [20-22]. A previous study on hepatocellular carcinoma reported that ciRS-7 could be considered a biomarker for microvascular invasion in hepatic cell carcinoma and a sponge for microRNA-7 [23].…”

Profiles and Bioinformatics Analysis of Differentially Expressed Circrnas in Taxol-Resistant Non-Small Cell Lung Cancer Cells

“…CircRNAs are also of paramount importance in many kinds of diseases and tumorigenesis. For instance, ciRS-7 depletion indirectly leads to a reduction of the ubiquitin conjugating enzyme UBE2A via excessive miRNA-7 in Alzheimer's disease [49]. The upregulation of hsa_circ_001569 and hsa_circ_0000069 augments cell proliferation, migration, and invasion, and hsa_circ_001988 downregulation is used as an indicator in colorectal cancer [50][51][52].…”

Noncoding RNAs in Alzheimer's disease

“…However, one circRNA, ciRS‐7 , which acts as a sponge of miR‐7, was found to be lower in sporadic AD, as determined in the hippocampal CA1 region (Lukiw, ). In keeping with the idea that downregulation of ciRS‐7 may affect the availability of miR‐7 and hence the fate of miR‐7 target mRNAs, enhanced miR‐7 activity in AD brain due to low ciRS‐7 levels decreased the production of AD‐relevant miR‐7 targets, including the ubiquitin‐conjugating enzyme UBE2A and epidermal growth factor receptor (Zhao, Alexandrov, Jaber, & Lukiw, ). Furthermore, in SH‐SY5Y cells, ciRS‐7 was recently found to promote the degradation of APP and BACE1 in an NF‐κB‐dependent manner (Shi et al, ).…”