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Acta Neuropathol. 2019 Apr 1. doi: 10.1007/s00401-019-01998-x. [Epub ahead of print]

FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy.

Author information

1
Technische Universität Dresden, Center for Regenerative Therapies Dresden, Fetscherstr. 105, 01307, Dresden, Germany.
2
Max Planck Institute for Molecular Biomedicine, Bioanalytical Mass Spectrometry, Röntgenstr. 20, 48149, Münster, Germany.
3
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307, Dresden, Germany.
4
Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany.
5
Division of Child Neurology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
6
Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
7
Verge Genomics, San Francisco, CA, USA.
8
The Bioinformatics CRO, Niceville, FL, USA.
9
Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
10
Dipartimento di Scienze Farmacologiche e Biomolecolari, Centre of Excellence on Neurodegenerative Diseases Università degli studi di Milano, Milan, 20133, Italy.
11
Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
12
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
13
Technische Universität Dresden, Center for Regenerative Therapies Dresden, Fetscherstr. 105, 01307, Dresden, Germany. jared.sterneckert@tu-dresden.de.

Abstract

Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by motor neuron degeneration and associated with aggregation of nuclear RNA-binding proteins (RBPs), including FUS. How FUS aggregation and neurodegeneration are prevented in healthy motor neurons remain critically unanswered questions. Here, we use a combination of ALS patient autopsy tissue and induced pluripotent stem cell-derived neurons to study the effects of FUS mutations on RBP homeostasis. We show that FUS' tendency to aggregate is normally buffered by interacting RBPs, but this buffering is lost when FUS mislocalizes to the cytoplasm due to ALS mutations. The presence of aggregation-prone FUS in the cytoplasm causes imbalances in RBP homeostasis that exacerbate neurodegeneration. However, enhancing autophagy using small molecules reduces cytoplasmic FUS, restores RBP homeostasis and rescues motor function in vivo. We conclude that disruption of RBP homeostasis plays a critical role in FUS-ALS and can be treated by stimulating autophagy.

KEYWORDS:

Amyotrophic lateral sclerosis; FUS; Induced pluripotent stem cells; Phase transition; Protein homeostasis; RNA-binding proteins

PMID:
30937520
DOI:
10.1007/s00401-019-01998-x

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