Physiological and pathological significance of tRNA fragments in hereditary neurodegenerative diseases

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17366
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Oita University
• Principal Investigator: Inoue Masanori 大分大学, 医学部, 助教 (20726913)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 橋小脳低形成10型 / tRNA fragment / 神経細胞死 / p53 / PKM2 / ゼブラフィッシュ

Outline of Final Research Achievements

We investigated the molecular mechanism of neuronal cell death induced by 5' tRNA fragments derived from tyrosine pre-tRNA (5' Tyr-tRF).From the modified version of the drug affinity responsive target stability (DARTS) approach, we identified pyruvate kinase M2 (PKM2). We injected PKM2 mRNA transcribed in vitro together with 5' Tyr-tRF into one-cell zebrafish embryos. Surprisingly, PKM2 mRNA specifically prevented the abnormal development from 5' Tyr-tRF toxicity. The PKM2 mRNA injection selectively prevented microcephaly and spinal motor neuron loss induced by 5' Tyr-tRF injection. We verified the interaction between the 5' Tyr-tRF and PKM2 by a pull-down assay. 5' Tyr-tRF showed much higher interaction with PKM2. These dates suggest that 5' Tyr-tRF interacts directly with PKM2 and may inhibit the PKM2-related signaling pathway.

Free Research Field

小児科学

Academic Significance and Societal Importance of the Research Achievements

本研究は、神経変性疾患の病因となり得るチロシンtRNA前駆体から由来の5 '側のエクソン断片（5' Tyr-tRF）とPKM2の関連性を明らかにした。 5' Tyr-tRFの蓄積は、橋小脳低形成10型の細胞だけでなく、酸化ストレスに応答した野生型細胞でも観察されることが分かっている。そのため、5' Tyr-tRFはアルツハイマー病、筋萎縮性側索硬化症、パーキンソン病などの他の神経変性疾患の病因に関与している可能性があると推測される。5' Tyr-tRFとPKM2は、これらの神経変性疾患の診断や治療のための、標的分子になり得る可能性がある。