title: Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS.
abstract: Amyotrophic lateral sclerosis (ALS) is a heterogeneous degenerative motor neuron disease linked to numerous genetic mutations in apparently unrelated proteins. These proteins, including SOD1, TDP-43, and FUS, are highly aggregation-prone and form a variety of intracellular inclusion bodies that are characteristic of different neuropathological subtypes of the disease. Contained within these inclusions are a variety of proteins that do not share obvious characteristics other than coaggregation. However, recent evidence from other neurodegenerative disorders suggests that disease-affected biochemical pathways can be characterized by the presence of proteins that are supersaturated, with cellular concentrations significantly greater than their solubilities. Here, we show that the proteins that form inclusions of mutant SOD1, TDP-43, and FUS are not merely a subset of the native interaction partners of these three proteins, which are themselves supersaturated. To explain the presence of coaggregating proteins in inclusions in the brain and spinal cord, we observe that they have an average supersaturation even greater than the average supersaturation of the native interaction partners in motor neurons, but not when scores are generated from an average of other human tissues. These results suggest that inclusion bodies in various forms of ALS result from a set of proteins that are metastable in motor neurons, and thus prone to aggregation upon a disease-related progressive collapse of protein homeostasis in this specific setting.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; jyerbury@uow.edu.au prc9015@nyp.org.|Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208-3500.|Department of Medicine, Columbia University College of Physicans & Surgeons, New York, NY 10032-3784.
authors.forename: Prajwal
authors.initials: P
authors.lastname: Ciryam
authors.affiliation: Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, United Kingdom.|Illawarra Health and Medical Research Institute, Wollongong, NSW 2522 Australia.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522 Australia.|Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
authors.forename: Isabella A
authors.initials: IA
authors.lastname: Lambert-Smith
authors.affiliation: Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, United Kingdom.|Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Bean
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Rosie
authors.initials: R
authors.lastname: Freer
authors.affiliation: Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain.|Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Cid
authors.affiliation: Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain.|Universitat Pompeu Fabra, 08003 Barcelona, Spain.|Institucio Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain.
authors.forename: Gian Gaetano
authors.initials: GG
authors.lastname: Tartaglia
authors.affiliation: Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Darren N
authors.initials: DN
authors.lastname: Saunders
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, NSW 2522 Australia.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522 Australia.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wilson
authors.affiliation: Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, United Kingdom.|Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
authors.forename: Stephen G
authors.identifier: 0000-0003-3410-6439
authors.initials: SG
authors.lastname: Oliver
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208-3500.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.affiliation: Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, United Kingdom.|Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Favrin
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, NSW 2522 Australia; jyerbury@uow.edu.au prc9015@nyp.org.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522 Australia.
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Yerbury
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000502:physiology; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D066329:Protein Aggregates / Q000502:physiology; D066263:Protein Aggregation, Pathological / Q000378:metabolism / Q000503:physiopathology*; D017510:Protein Folding; D034702:RNA-Binding Protein FUS / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013127:Spinal Nerves / Q000378:metabolism / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C000599550:FUS protein, human; D066329:Protein Aggregates; D034702:RNA-Binding Protein FUS; C000598624:TARDBP protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: motor neuron disease; protein aggregation; protein homeostasis; protein misfolding; supersaturation