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Aggregation-triggering segments of SOD1 fibril formation support a common pathway for familial and sporadic ALS

Ivanova, Magdalena I. and Sievers, Stuart A. and Guenther, Elizabeth L. and Johnson, Lisa M. and Winkler, Duane D. and Galaleldeen, Ahmad and Sawaya, Michael R. and Hart, P. John and Eisenberg, David S. (2014) Aggregation-triggering segments of SOD1 fibril formation support a common pathway for familial and sporadic ALS. Proceedings of the National Academy of Sciences of the United States of America, 111 (1). pp. 197-201. ISSN 0027-8424. PMCID PMC3890817. doi:10.1073/pnas.1320786110.

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ALS is a terminal disease of motor neurons that is characterized by accumulation of proteinaceous deposits in affected cells. Pathological deposition of mutated Cu/Zn superoxide dismutase (SOD1) accounts for ∼20% of the familial ALS (fALS) cases. However, understanding the molecular link between mutation and disease has been difficult, given that more than 140 different SOD1 mutants have been observed in fALS patients. In addition, the molecular origin of sporadic ALS (sALS) is unclear. By dissecting the amino acid sequence of SOD1, we identified four short segments with a high propensity for amyloid fibril formation. We find that fALS mutations in these segments do not reduce their propensity to form fibrils. The atomic structures of two fibril-forming segments from the C terminus, ^(101)DSVISLS^(107) and ^(147)GVIGIAQ^(153), reveal tightly packed β-sheets with steric zipper interfaces characteristic of the amyloid state. Based on these structures, we conclude that both C-terminal segments are likely to form aggregates if available for interaction. Proline substitutions in 101DSVISLS107 and ^(147)GVIGIAQ^(153) impaired nucleation and fibril growth of full-length protein, confirming that these segments participate in aggregate formation. Our hypothesis is that improper protein maturation and incompletely folded states that render these aggregation-prone segments available for interaction offer a common molecular pathway for sALS and fALS.

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Additional Information:© 2014 National Academy of Sciences. Contributed by David Eisenberg, November 12, 2013 (sent for review December 11, 2012). We thank Dr. L. Goldschmidt, Dr. M. Chattopadhyay, Dr. R. Nelson, Dr. B. Chan, and Prof. J. S. Valentine for discussions; Dr. I. Kourinov, Dr. J. Schuermann, Dr. K. Rajashankar, Dr. N. Sukumar, and Dr. S. Banerjee at Advanced Photon Source beamline 24-ID-E and European Synchrotron Radiation Facility beamline ID13 for help with X-ray data collection; Howard Hughes Medical Institute, P01 NS049134, National Institutes of Health AG029430, NIH P01, and Department of Energy for support to the D.E. laboratory; and Department of Veterans Affairs 1I01BX000506, the Judith and Jean Pape Adams Charitable Foundation, and NIH R01 NS39112 for support to the P.J.H. laboratory. Author contributions: M.I.I., S.A.S., D.D.W., A.G., M.R.S., P.J.H., and D.S.E. designed research; M.I.I., S.A.S., E.L.G., L.M.J., D.D.W., and A.G. performed research; M.I.I., S.A.S., E.L.G., M.R.S., P.J.H., and D.S.E. analyzed data; and M.I.I., S.A.S., L.M.J., D.D.W., M.R.S., P.J.H., and D.S.E. wrote the paper. The authors declare no conflict of interest.
Funding AgencyGrant Number
NIHP01 NS049134
NIHP01 AG029430
Department of Energy (DOE)UNSPECIFIED
Department of Veterans Affairs1I01BX000506
Judith and Jean Pape Adams Charitable FoundationUNSPECIFIED
NIHR01 NS39112
Howard Hughes Medical InstituteUNSPECIFIED
Subject Keywords:protein aggregation; peptide structure; amyotrophic lateral sclerosis
Issue or Number:1
PubMed Central ID:PMC3890817
Record Number:CaltechAUTHORS:20140214-090621913
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Official Citation: Magdalena I. Ivanova, Stuart A. Sievers, Elizabeth L. Guenther, Lisa M. Johnson, Duane D. Winkler, Ahmad Galaleldeen, Michael R. Sawaya, P. John Hart, and David S. Eisenberg Aggregation-triggering segments of SOD1 fibril formation support a common pathway for familial and sporadic ALS PNAS 2014 111 (1) 197-201; published ahead of print December 16, 2013, doi:10.1073/pnas.1320786110
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:43828
Deposited By: Ruth Sustaita
Deposited On:18 Feb 2014 15:58
Last Modified:10 Nov 2021 16:43

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