News Release

Predicting patient survival from protein stability and aggregation propensity

Peer-Reviewed Publication

PLOS

Amyotrophic Lateral Sclerosis (ALS), also known in America as Lou Gehrig's disease, is a fatal neurodegenerative disease that has no effective treatment. While it is well known that specific genetic mutations can cause the condition, how the changed genes produce the symptoms has previously been a mystery. A new paper in this week's PLoS Biology, the online open access journal, is able to predict ALS patient longevity to an unprecedented degree based on two properties of the protein SOD1. Jeffrey Agar and colleagues at Brandeis and Harvard Universities show that both the stickiness of SOD1 and its decreased stability accounts for 69% of patient survival data, providing strong evidence that SOD1 protein stability and its aggregation propensity are the main toxic causes of ALS.

ALS can occur spontaneously in people with no family history of the condition, but about 10% of cases run in families, and it has been shown that in about 20% of this subset of cases the underlying mutation is a change in the gene for SOD1. SOD1 is an enzyme – a biological catalyst – that neutralises potentially dangerous molecules, but ALS-causing mutant enzymes gain an unknown toxic function – i.e. the disease occurs because SOD1 does something that it doesn't do in unaffected people.

SOD1 has been shown to be mutated in at least 119 different ways in different ALS patients. Some mutations will have a more dramatic effect on SOD1 structure than others. SOD1 – like all enzymes – is a string of different amino acids in a certain pattern. Mutations that switch an amino acid for one with very different properties, or which alter an amino acid crucial for the formation of certain structural regions of the enzyme, will have a large impact on SOD1 function. Agar et al. looked at the difference in disease progression for a large population of patients with differing mutations, and found that those mutations which made SOD1 more likely to unfold from its normal structure, and those mutations that made it more likely that SOD1 would stick to other unfolded SOD1 molecules, correlated with reduced survival times post disease onset. Thus Agar et al. conclude that in people with ALS, it is the sticking together of SOD1 that is toxic.

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Citation: Wang Q, Johnson JL, Agar NYR, Agar JN (2008) Protein aggregation and protein instability govern familial amyotrophic lateral sclerosis patient survival. PLoS Biol 6(7): e170. doi:10.1371/journal.pbio.0060170

PLEASE ADD THE LINK TO THE PUBLISHED ARTICLE IN ONLINE VERSIONS OF YOUR REPORT: http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0060170

PRESS ONLY PREVIEW OF THE ARTICLE: http://www.plos.org/press/plbi-06-07-agar.pdf

CONTACT:
Jeffry N. Agar
Brandeis University
Department of Chemistry
Waltham, MA 02454
+1-781-736-2425
agar@brandeis.edu


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