FUS Interacts with ATP Synthase Beta Subunit and Induces Mitochondrial Unfolded Protein Response in Cellular and Animal Models

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2018 Sep 26

PMID 30249657

Citations 68

Authors

Jianwen Deng

Peng Wang

Xiaoping Chen

Haipeng Cheng

Jianghong Liu

Kazuo Fushimi

Li Zhu

Jane Y Wu

Affiliations

Soon will be listed here.

Abstract

FUS (fused in sarcoma) proteinopathy is a group of neurodegenerative diseases characterized by the formation of inclusion bodies containing the FUS protein, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Previous studies show that mitochondrial damage is an important aspect of FUS proteinopathy. However, the molecular mechanisms by which FUS induces mitochondrial damage remain to be elucidated. Our biochemical and genetic experiments demonstrate that FUS interacts with the catalytic subunit of mitochondrial ATP synthase (ATP5B), disrupts the formation of ATP synthase complexes, and inhibits mitochondrial ATP synthesis. FUS expression activates the mitochondrial unfolded protein response (UPR). Importantly, down-regulating expression of ATP5B or UPR genes in FUS transgenic flies ameliorates neurodegenerative phenotypes. Our data show that mitochondrial impairment is a critical early event in FUS proteinopathy, and provide insights into the pathogenic mechanism of FUS-induced neurodegeneration.

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