ストレスで疲弊した脳細胞が神経変性疾患の根本原因か?(Are stressed-out brain cells the root cause of neurodegenerative disease?)

2024-02-13 カリフォルニア大学バークレー校(UCB)

<関連情報>

• https://news.berkeley.edu/2024/02/13/are-stressed-out-brain-cells-the-root-cause-of-neurodegenerative-disease
• https://www.nature.com/articles/s41586-023-06985-7

神経変性で変異したE3リガーゼがストレス応答を抑制することを発見 Stress response silencing by an E3 ligase mutated in neurodegeneration

Diane L. Haakonsen,Michael Heider,Andrew J. Ingersoll,Kayla Vodehnal,Samuel R. Witus,Takeshi Uenaka,Marius Wernig & Michael Rapé
Nature  Published:31 January 2024
DOI:https://doi.org/10.1038/s41586-023-06985-7

Abstract

Stress response pathways detect and alleviate adverse conditions to safeguard cell and tissue homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health^1,2,3. How stress responses are turned off at the right time and place remains poorly understood. Here we report a ubiquitin-dependent mechanism that silences the cellular response to mitochondrial protein import stress. Crucial to this process is the silencing factor of the integrated stress response (SIFI), a large E3 ligase complex mutated in ataxia and in early-onset dementia that degrades both unimported mitochondrial precursors and stress response components. By recognizing bifunctional substrate motifs that equally encode protein localization and stability, the SIFI complex turns off a general stress response after a specific stress event has been resolved. Pharmacological stress response silencing sustains cell survival even if stress resolution failed, which underscores the importance of signal termination and provides a roadmap for treating neurodegenerative diseases caused by mitochondrial import defects.