lncRNA Neat1 regulates neuronal dysfunction post-sepsis via stabilization of hemoglobin subunit beta

Mol Ther. 2022 Jul 6;30(7):2618-2632. doi: 10.1016/j.ymthe.2022.03.011. Epub 2022 Mar 21.

Abstract

Sepsis-associated encephalopathy (SAE) is characterized by acute and diffuse brain dysfunction and correlates with long-term cognitive impairments with no targeted therapy. We used a mouse model of sepsis-related cognitive impairment to examine the role of lncRNA nuclear enriched abundant transcript 1 (Neat1) in SAE. We observed that Neat1 expression was increased in neuronal cells from septic mice and that it directly interacts with hemoglobin subunit beta (Hbb), preventing its degradation. The Neat1/Hbb axis suppressed postsynaptic density protein 95 (PSD-95) levels and decreased dendritic spine density. Neat1 knockout mice exhibited decreased Hbb levels, which resulted in increased PSD-95 levels, increased neuronal dendritic spine density, and decreased anxiety and memory impairment. Neat1 silencing via the antisense oligonucleotide GapmeR ameliorated anxiety-like behavior and cognitive impairment post-sepsis. In conclusion, we uncovered a previously unknown mechanism of the Neat1/Hbb axis in regulating neuronal dysfunction, which may lead to a novel treatment strategy for SAE.

Keywords: Hbb; Neat1; PSD-95; antisense oligonucleotide; cognitive impairment; sepsis-associated encephalopathy; synaptic dysfunction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Hemoglobin Subunits
  • Mice
  • Mice, Knockout
  • MicroRNAs* / genetics
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism
  • Sepsis* / complications
  • Sepsis* / genetics

Substances

  • Hemoglobin Subunits
  • MicroRNAs
  • RNA, Long Noncoding