Characterization of a G-Quadruplex Structure in Pre-miRNA-1229 and in Its Alzheimer's Disease-Associated Variant rs2291418: Implications for miRNA-1229 Maturation

Int J Mol Sci. 2020 Jan 24;21(3):767. doi: 10.3390/ijms21030767.

Abstract

Alzheimer's disease (AD), the most common age-related neurodegenerative disease, is associated with various forms of cognitive and functional impairment that worsen with disease progression. AD is typically characterized as a protein misfolding disease, in which abnormal plaques form due to accumulation of tau and β-amyloid (Aβ) proteins. An assortment of proteins is responsible for the processing and trafficking of Aβ, including sortilin-related receptor 1 (SORL1). Recently, a genome-wide association study of microRNA-related variants found that a single nucleotide polymorphism (SNP) rs2291418 within premature microRNA-1229 (pre-miRNA-1229) is significantly associated with AD. Moreover, the levels of the mature miRNA-1229-3p, which has been shown to regulate the SORL1 translation, are increased in the rs2291418 pre-miRNA-1229 variant. In this study we used various biophysical techniques to show that pre-miRNA-1229 forms a G-quadruplex secondary structure that coexists in equilibrium with the canonical hairpin structure, potentially controlling the production of the mature miR-1229-3p, and furthermore, that the AD-associated SNP rs2291418 pre-miR-1229 changes the equilibrium between these structures. Thus, the G-quadruplex structure we identified within pre-miRNA-1229 could potentially act as a novel therapeutic target in AD.

Keywords: Alzheimer’s disease; RNA G-quadruplex; pre-miRNA-1229; rs2291418.

MeSH terms

  • Alzheimer Disease*
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism
  • G-Quadruplexes*
  • Humans
  • MicroRNAs / chemistry*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Nucleic Acid Conformation*
  • Polymorphism, Single Nucleotide*

Substances

  • Amyloid beta-Peptides
  • MIRN1229 microRNA, human
  • MicroRNAs