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Additional file 2. Supplemental Table 1.

Additional file 1. Supplemental Methods.

Additional file 3. Supplemental Figures.

The construction and analysis of networks is increasingly widespread in biological research. We have developed esyN ("easy networks") as a free and open source tool to facilitate the exchange of biological network models between researchers. esyN acts as a searchable database of user-created networks from any field. We have developed a simple companion web tool that enables users to view and edit networks using data from publicly available databases. Both normal interaction networks (graphs) and Petri nets can be created. In addition to its basic tools, esyN contains a number of logical templates that can be used to create models more easily. The ability to use previously published models as building blocks makes esyN a powerful tool for the construction of models and network graphs. Users are able to save their own projects online and share them either publicly or with a list of collaborators. The latter can be given the ability to edit the network themselves, allowing online collaboration on network construction. esyN is designed to facilitate unrestricted exchange of this increasingly important type of biological information. Ultimately, the aim of esyN is to bring the advantages of Open Source software development to the construction of biological networks.

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., P.C. was supported by grants from the US-UK Fulbright Commission, St. John’s College, University of Cambridge, and NIH (Northwestern University Medical Scientist Training Program Grant T32 GM8152-28). I.A.L.-S. was supported by Rotary Health Australia. D.M.B., S.G.O., and G.F. were supported by the Wellcome Trust/Medical Research Council (Grant Code 089703/Z/09/Z). D.N.S. was supported by a National Health and Medical Research Council (NHMRC) Project grant. R.I.M. was supported by grants from the NIH (National Institute of General Medical Sciences, National Institute on Aging, and National Institute of Neurological Disorders and Stroke), Ellison Medical Foundation, Glenn Foundation, and Daniel F. and Ada L. Rice Foundation. C.M.D. and M.V. are members of the Cambridge Centre for Misfolding Diseases and were supported by the Wellcome Trust. J.J.Y. was supported by grants from the NHMRC (Grants 1095215 and 1084144), Motor Neuron Disease Research Institute of Australia, and Australian Research Council (Grant DE120102840). F.C. and G.G.T. acknowledge support from the European Research Council (RIBOMYLOME_309545) and Spanish Ministry of Economy and Competitiveness (BFU2014-55054-P).