FUS Interacts with HSP60 to Promote Mitochondrial Damage.
FUS-proteinopathies, a group of heterogeneous disorders including ALS-FUS and FTLD-FUS, are characterized by the formation of inclusion bodies containing the nuclear protein FUS in the affected patients. However, the underlying molecular and cellular defects remain unclear. Here we provide evidence for mitochondrial localization of FUS and its induction of mitochondrial damage. Remarkably, FTLD-FUS brain samples show increased FUS expression and mitochondrial defects. Biochemical and genetic data demonstrate that FUS interacts with a mitochondrial chaperonin, HSP60, and that FUS translocation to mitochondria is, at least in part, mediated by HSP60. Down-regulating HSP60 reduces mitochondrially localized FUS and partially rescues mitochondrial defects and neurodegenerative phenotypes caused by FUS expression in transgenic flies. This is the first report of direct mitochondrial targeting by a nuclear protein associated with neurodegeneration, suggesting that mitochondrial impairment may represent a critical event in different forms of FUS-proteinopathies and a common pathological feature for both ALS-FUS and FTLD-FUS. Our study offers a potential explanation for the highly heterogeneous nature and complex genetic presentation of different forms of FUS-proteinopathies. Our data also suggest that mitochondrial damage may be a target in future development of diagnostic and therapeutic tools for FUS-proteinopathies, a group of devastating neurodegenerative diseases.
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
Jianwen
J
Deng
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China; Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Mengxue
M
Yang
Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America; National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Science and Peking Union Medical College, Tsinghua University, Beijing, China.
Yanbo
Y
Chen
Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Xiaoping
X
Chen
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Jianghong
J
Liu
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Shufeng
S
Sun
Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Haipeng
H
Cheng
Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America; School of Electronic Science and Engineering, Nanjing University, Nanjing, China.
Yang
Y
Li
Department of Pathology & Neurology, The Cognitive Neurology& Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Eileen H
EH
Bigio
Department of Pathology & Neurology, The Cognitive Neurology& Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Marsel
M
Mesulam
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Science and Peking Union Medical College, Tsinghua University, Beijing, China.
Qi
Q
Xu
School of Electronic Science and Engineering, Nanjing University, Nanjing, China.
Sidan
S
Du
Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Kazuo
K
Fushimi
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Li
L
Zhu
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Jane Y
JY
Wu
D000818:Animals; D030801:Animals, Genetically Modified; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000378:metabolism*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism
D018834:Chaperonin 60; D029721:Drosophila Proteins; C439908:FUS protein, Drosophila; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; D017382:Reactive Oxygen Species