Author: Nikolay Dokholyan
Position: Assistant Professor
Institution: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill
E-mail: dokh@med.unc.edu
Additional Authors: Sagar Khare, Michael Caplow
Submitted Date: July 31, 2008
Published Date: August 1, 2008
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

Wang et al. have provided interesting new information in which they correlate earlier biochemical studies of the aggregation properties of wild-type and mutant SOD1 with patient-survival data. The work confirms and provides further epidemiologic support to a significant body of biochemical work demonstrating that protein aggregation is indeed linked to FALS.

For example, in 2004, Khare et al. showed that dimer dissociation, loss of metals from SOD monomers and their subsequent aggregation leads to the formation of amyloid-like fibrils, also observed in FALS (1). In 2006, Khare et al. reported results from a large-scale in silico stability analysis on ~100 FALS-associated SOD mutations, and suggested that FALS mutations decrease the stability of apo-SOD, and increase its dimer-dissociation propensity (2). Khare et al. also showed that native-state dynamics of apo-SOD dimers and monomers suggests that mutations destabilize key structural lynchpins required to maintain fold-fidelity, thereby providing a microscopic mechanism for the thermodynamic observations that they and others have made (3-8). Khare et al. further published a review in 2006 where Khare et al. tied these and other observations to general frameworks for understanding protein aggregation, and in that review suggested that protein instability was one of the major factors leading to FALS-associated aggregation in SOD (9).

REFERENCES:

(1) S. D. Khare, M. Caplow, and N. V. Dokholyan, "The rate and equilibrium constants for a multi-step reaction sequence for the aggregation of superoxide dismutase in ALS" Proceedings of the National Academy of Sciences USA, 101: 15094-15099 (2004).

(2) S. D. Khare, M. Caplow, and N. V. Dokholyan, "FALS mutations in Cu, Zn superoxide dismutase destabilize the dimer and increase dimer dissociation propensity: a large-scale thermodynamic analysis"Amyloid: the Journal of Protein Folding Disorders, 13: 226 - 235 (2006).

(3) S. D. Khare and N. V. Dokholyan, "Common dynamical signatures of FALS-associated structurally-diverse Cu, Zn superoxide dismutase mutants" Proceedings of the National Academy of Sciences USA,103: 3147-3152 (2006).

(4) Rodriguez JA, Valentine JS, Eggers DK, Roe JA, Tiwari A, et al. “Familial amyotrophic lateral sclerosis-associated mutations decrease the thermal stability of distinctly metallated species of human copper/zinc superoxide dismutase.” J Biol Chem 277: 15932–15937 (2002).

(5) Lindberg MJ, Tibell L, Oliveberg M “Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: decreased stability of the apo state.” Proc Natl Acad Sci U S A 99: 16607–16612 (2002).

(6) Hough MA, Grossmann JG, Antonyuk SV, Strange RW, Doucette PA, et al. “Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants.” Proc Natl Acad Sci U S A 101: 5976–5981 (2004).

(7) Stathopulos PB, Rumfeldt JA, Scholz GA, Irani RA, Frey HE, et al. Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis show enhanced formation of aggregates in vitro. Proc Natl Acad Sci U S A 100: 7021–7026 (2003).

(8) DiDonato M, Craig L, Huff ME, Thayer MM, Cardoso RM, et al. ALS mutants of human superoxide dismutase form fibrous aggregates via framework destabilization. J Mol Biol 332: 601–615 (2003).

(9) S. D. Khare and N. V. Dokholyan, "Molecular mechanisms of polypeptide aggregation in human diseases" Current Protein & Peptide Science, 8: 573-579 (2007).