FUS ALS neurons activate major stress pathways and reduce translation as an early protective mechanism against neurodegeneration
Barbara Szewczyk,
René Günther,
Julia Japtok,
Moritz J. Frech,
Marcel Naumann,
Hyun O. Lee,
Andreas Hermann
Affiliations
Barbara Szewczyk
Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
René Günther
Department of Neurology, Technische Universität Dresden, Dresden, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Dresden, Dresden, Germany
Julia Japtok
Department of Neurology, Technische Universität Dresden, Dresden, Germany
Moritz J. Frech
Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
Marcel Naumann
Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
Hyun O. Lee
Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Andreas Hermann
Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald, Rostock, Germany; Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, Rostock, Germany; Corresponding author
Summary: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder causing progressive loss of motor neurons. Mutations in Fused in sarcoma (FUS) leading to its cytoplasmic mislocalization cause a subset of ALS. Under stress, mutant FUS localizes to stress granules (SGs)—cytoplasmic condensates composed of RNA and various proteins. Aberrant dynamics of SGs is linked to the pathology of ALS. Here, using motor neurons (MNs) derived from human induced pluripotent stem cells, we show that, in mutant FUS, MN dynamics of SGs is disturbed. Additionally, heat-shock response (HSR) and integrated stress response (ISR) involved in the regulation of SGs are upregulated in mutant MNs. HSR activation correlates with the amount of cytoplasmic FUS mislocalization. While inhibition of SG formation, translation, or ISR does not influence survival of FUS ALS neurons, proteotoxicity that cannot be compensated with the activation of stress pathways is the main driver of neurodegeneration in early FUS ALS.
