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.
journal_name
Proc Natl Acad Sci U S Aauthors
Ciryam P,Lambert-Smith IA,Bean DM,Freer R,Cid F,Tartaglia GG,Saunders DN,Wilson MR,Oliver SG,Morimoto RI,Dobson CM,Vendruscolo M,Favrin G,Yerbury JJdoi
10.1073/pnas.1613854114subject
Has Abstractpub_date
2017-05-16 00:00:00pages
E3935-E3943issue
20eissn
0027-8424issn
1091-6490pii
1613854114journal_volume
114pub_type
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