Nonamyloid aggregates arising from mature copper/zinc superoxide dismutases resemble those observed in amyotrophic lateral sclerosis |
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Authors: | Hwang Young-Mi Stathopulos Peter B Dimmick Kristin Yang Hong Badiei Hamid R Tong Ming Sze Rumfeldt Jessica A O Chen Pu Karanassios Vassili Meiering Elizabeth M |
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Affiliation: | Department of Chemistry and Biology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada. |
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Abstract: | Protein aggregation is a hallmark of many diseases, including amyotrophic lateral sclerosis (ALS) where aggregation of copper/zinc superoxide dismutase (SOD1) is implicated in pathogenesis. We report here that fully metallated (holo) SOD1 under physiologically relevant solution conditions can undergo changes in metallation and/or dimerization over time and form aggregates that do not exhibit classical characteristics of amyloid. The relevance of the observed aggregation to disease is demonstrated by structural and tinctorial analyses, including the novel observation of binding of an anti-SOD1 antibody that specifically recognizes aggregates in ALS patients and mice models. ALS-associated SOD1 mutations can promote aggregation but are not essential. The SOD1 aggregation is characterized by a lag phase, which is diminished by self- or cross-seeding and by heterogeneous nucleation. We interpret these findings in terms of an expanded aggregation mechanism consistent with other in vitro and in vivo findings that point to multiple pathways for the formation of toxic aggregates by different forms of SOD1. |
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Keywords: | Amyotropic Lateral Sclerosis (Lou Gehrig Disease) Neurological Diseases Protein Assembly Protein-Protein Interactions Superoxide Dismutase (SOD) SEDI Seeding Effects |
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