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LncRNA CRNDE binds hnRNPA1 to facilitate carbon monoxide poisoning-induced delayed encephalopathy via inhibiting UCHL5-mediated SMO deubiquitination

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Abstract

Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is one of the most common complications following carbon monoxide intoxication. Long noncoding RNAs (lncRNAs) exert critical functions in numerous neurological disorders. We intended to investigate the role of CRNDE in DEACMP. The DEACMP model in rats and the oxygen–glucose deprivation/reoxygenation (OGD/R) model in PC-12 cells were established. Brain and cell injuries were assessed with H&E staining, Nissl staining, TUNEL and CCK8 assays, respectively. Related proteins and RNAs were quantified with western blot and qRT-PCR. The N6-methyladenosine (m6A) level was determined using MeRIP-qPCR and immunofluorescence. Loss and gain function studies were performed to investigate the biological function of CRNDE. The potential mechanisms between each factor were explored using RNA immunoprecipitation, RNA-pull down and co-immunoprecipitation. CRNDE was increased in the hippocampal tissues of DEACMP rats and in OGD/R-treated PC-12 cells, which was positively correlated to m6A modification. Knockdown of CRNDE reduced cell damage and elevated UCHL5 and SMO expressions in OGD/R-treated PC-12 cells. hnRNPA1 was upregulated in DEACMP. In addition, inhibiting hnRNPA1 prevented apoptosis in PC-12 cells subjected to OGD/R. hnRNPA1 bound to CRNDE and remained in the nucleus, which inhibited UCHL5 expression through the formation of CRNDE-hnRNPA1-mRNA complex. UCHL5 could inhibit SMO ubiquitination and suppress PC-12 cell apoptosis during OGD/R. CRNDE silencing blocked brain injury in DEACMP, while knocking down UCHL5 reversed these effects. CRNDE interacted with hnRNPA1 to facilitate DEACMP via inhibition of UCHL5-mediated SMO deubiquitination. CRNDE might be a latent therapeutic target for treating DEACMP.

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Data availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

DEACMP :

Delayed encephalopathy after acute carbon monoxide poisoning

lncRNAs :

Long noncoding RNAs

OGD/R :

Oxygen-glucose deprivation/reoxygenation

m6A :

N6-methyladenosine

hnRNPA1 :

Heterogeneous nuclear ribonuclear protein A1

UCHL5 :

Ubiquitin C-terminal hydrolase L5

Shh :

Sonic hedgehog

SMO :

Smoothened

CO :

Carbon monoxide

AAV9 :

Adeno-associated virus 9

FBS :

Fetal bovine serum

NGF :

Nerve growth factor

H&E :

Hematoxylin and eosin

qRT-PCR :

Reverse transcription quantitative polymerase chain reaction

3'-UTR :

3' Untranslated regions

CDS :

Coding sequence

CCK8 :

Cell counting kit-8

LDH :

Lactate dehydrogenase

RIP :

RNA immunoprecipitation

MeRIP-qPCR :

M6A-RNA immunoprecipitation and qPCR

ANOVA :

One-way analysis of variance

AKT :

Protein kinase 3

GSK3β :

Glycogen synthase kinase 3beta

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Acknowledgements

We would like to give our sincere gratitude to the reviewers for their constructive comments.

Funding

This work was supported by Natural Science Foundation of Jilin Province (20200201339JC).

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Authors and Affiliations

  1. Department of Emergency, the First Hospital of Jilin University, No. 1 Xinmin Road, Changchun, 130021, Jilin Province, People’s Republic of China

    Zuolong Liu & Li Pang

  2. Department of Respiratory, Qianwei Hospital of Jilin Province, Changchun, 130012, Jilin Province, People’s Republic of China

    Miao Bian

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  1. Zuolong Liu
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  2. Miao Bian
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Contributions

Zuolong Liu: Conceptualization, Methodology, Writing- Original draft preparation, Investigation, Validation, Visualization.

Miao Bian: Software, Data curation.

Li Pang: Conceptualization, Supervision, Writing- Original draft preparation, Writing- Reviewing and Editing.

Corresponding author

Correspondence to Li Pang.

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All procedures were approved by the Animal Ethics Committee in the First Hospital of Jilin University.

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Liu, Z., Bian, M. & Pang, L. LncRNA CRNDE binds hnRNPA1 to facilitate carbon monoxide poisoning-induced delayed encephalopathy via inhibiting UCHL5-mediated SMO deubiquitination. Metab Brain Dis 38, 1097–1113 (2023). https://doi.org/10.1007/s11011-022-01157-4

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