Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2017 May 16;114(20):E3935-E3943. doi: 10.1073/pnas.1613854114. Epub 2017 Apr 10.

Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS.

Author information

1
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; jyerbury@uow.edu.au prc9015@nyp.org.
2
Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208-3500.
3
Department of Medicine, Columbia University College of Physicans & Surgeons, New York, NY 10032-3784.
4
Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
5
Illawarra Health and Medical Research Institute, Wollongong, NSW 2522 Australia.
6
School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522 Australia.
7
Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
8
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
9
Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain.
10
Universitat Pompeu Fabra, 08003 Barcelona, Spain.
11
Institucio Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain.
12
Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
13
Illawarra Health and Medical Research Institute, Wollongong, NSW 2522 Australia; jyerbury@uow.edu.au prc9015@nyp.org.

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.

KEYWORDS:

motor neuron disease; protein aggregation; protein homeostasis; protein misfolding; supersaturation

Comment in

PMID:
28396410
PMCID:
PMC5441770
DOI:
10.1073/pnas.1613854114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center