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Neuron. 2015 Nov 18;88(4):678-90. doi: 10.1016/j.neuron.2015.10.030. Epub 2015 Oct 29.

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function.

Author information

1
Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
2
Cambridge Institute for Medical Research, Cambridge National Institute for Health Research - Biomedical Research Unit in Dementia, University of Cambridge, Cambridge CB2 0XY, UK.
3
Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
4
Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK.
5
Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK; Centre for Genomic Regulation and University Pompeu Fabra, Dr. Aiguader St. 88, and Universitat Pompeu Fabra, 08003, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 23 Passeig Lluís Companys, 08010 Barcelona, Spain.
6
Cambridge Systems Biology Center & Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
7
Department of Research, Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
8
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
9
Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
10
Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA.
11
Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
12
Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada; Cambridge Institute for Medical Research, Cambridge National Institute for Health Research - Biomedical Research Unit in Dementia, University of Cambridge, Cambridge CB2 0XY, UK. Electronic address: phs22@cam.ac.uk.

Abstract

The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.

PMID:
26526393
PMCID:
PMC4660210
DOI:
10.1016/j.neuron.2015.10.030
[Indexed for MEDLINE]
Free PMC Article

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