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Tyrosine pre-transfer RNA fragments are linked to p53-dependent neuronal cell death via PKM2

Masanori Inoue1, Kazumasa Hada2, Hiroshi Shiraishi2

  • 1Department of Cell Biology, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan; Department of Pediatrics, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan.

Biochemical and Biophysical Research Communications
|March 8, 2020
PubMed

Insights

Specific transfer RNA fragments (tRNA fragments) linked to CLP1 gene mutations cause neurodegeneration. Tyrosine tRNA fragments (Tyr-tRF) induce cell death by interacting with pyruvate kinase M2 (PKM2), offering insights into neuronal disease mechanisms.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • Transfer RNA (tRNA) fragments are implicated in neurodegenerative disease pathogenesis.
  • CLP1 mutations cause pontocerebellar hypoplasia type-10, leading to tRNA fragment accumulation.
  • The specific tRNA fragments driving neuronal disease remain unidentified.

Purpose of the Study:

  • To identify which tRNA fragments resulting from CLP1 mutations most significantly impact neuronal disease onset.
  • To elucidate the molecular mechanisms linking specific tRNA fragments to neuronal cell death.

Main Methods:

  • Analysis of tRNA fragments generated by CLP1 mutations.
  • Assessing the impact of different tRNA fragments on neuronal cell death.
  • Investigating the interaction between 5' Tyr-tRF and pyruvate kinase M2 (PKM2).
  • Utilizing zebrafish models to study neuronal defects.

Main Results:

  • 5' tRNA fragments derived from tyrosine pre-tRNA (5' Tyr-tRF) induced p53-dependent neuronal cell death more than other fragments.
  • 5' Tyr-tRF was found to directly bind to PKM2.
  • PKM2 mRNA injection in zebrafish embryos rescued neuronal defects caused by 5' Tyr-tRF.

Conclusions:

  • 5' Tyr-tRF plays a significant role in CLP1 mutation-associated neuronal cell death.
  • PKM2 is a key regulator in the mechanism linking 5' Tyr-tRF to neuronal damage.
  • These findings provide a partial mechanistic understanding of tRNA fragments in neurodegeneration.
Keywords:
Neuronal cell deathPKM2p53tRNA fragments

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