PUBLICATION

Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish

Authors
Inoue, M., Miyahara, H., Shiraishi, H., Shimizu, N., Tsumori, M., Kiyota, K., Maeda, M., Umeda, R., Ishitani, T., Hanada, R., Ihara, K., Hanada, T.
ID
ZDB-PUB-210418-12
Date
2021
Source
Scientific Reports   11: 8392 (Journal)
Registered Authors
Hanada, Reiko, Hanada, Toshikatsu
Keywords
none
MeSH Terms
  • Anemia/enzymology
  • Anemia/etiology
  • Anemia/pathology*
  • Animals
  • Autophagy*
  • Leucine/metabolism*
  • Leucine-tRNA Ligase/deficiency*
  • Liver Failure/enzymology
  • Liver Failure/etiology
  • Liver Failure/pathology*
  • Zebrafish/growth & development*
  • Zebrafish/metabolism
(all 12)
PubMed
33863987 Full text @ Sci. Rep.
Abstract
Leucyl-tRNA synthetase (LARS) is an enzyme that catalyses the ligation of leucine with leucine tRNA. LARS is also essential to sensitize the intracellular leucine concentration to the mammalian target of rapamycin complex 1 (mTORC1) activation. Biallelic mutation in the LARS gene causes infantile liver failure syndrome type 1 (ILFS1), which is characterized by acute liver failure, anaemia, and neurological disorders, including microcephaly and seizures. However, the molecular mechanism underlying ILFS1 under LARS deficiency has been elusive. Here, we generated Lars deficient (larsb-/-) zebrafish that showed progressive liver failure and anaemia, resulting in early lethality within 12 days post fertilization. The atg5-morpholino knockdown and bafilomycin treatment partially improved the size of the liver and survival rate in larsb-/- zebrafish. These findings indicate the involvement of autophagy in the pathogenesis of larsb-/- zebrafish. Indeed, excessive autophagy activation was observed in larsb-/- zebrafish. Therefore, our data clarify a mechanistic link between LARS and autophagy in vivo. Furthermore, autophagy regulation by LARS could lead to development of new therapeutics for IFLS1.
Genes / Markers
Marker Marker Type Name
atg5GENEATG5 autophagy related 5 homolog (S. cerevisiae)
fabp10aGENEfatty acid binding protein 10a, liver basic
lars1aGENEleucyl-tRNA synthetase 1a
lars1bGENEleucyl-tRNA synthetase 1b
lars2GENEleucyl-tRNA synthetase 2, mitochondrial
1 - 5 of 5
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Figures
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
oi2TgTransgenic Insertion
    oi3
      Small Deletion
      1 - 2 of 2
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      Human Disease / Model
      Human Disease Fish Conditions Evidence
      infantile liver failure syndrome 1TAS
      1 - 1 of 1
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      Sequence Targeting Reagents
      Target Reagent Reagent Type
      atg5MO1-atg5MRPHLNO
      lars1bCRISPR2-lars1bCRISPR
      1 - 2 of 2
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      Fish
      Antibodies
      Orthology
      No data available
      Engineered Foreign Genes
      Marker Marker Type Name
      mCherryEFGmCherry
      1 - 1 of 1
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      Mapping