Monomeric Cu,Zn-superoxide Dismutase Is a Common Misfolding Intermediate in the Oxidation Models of Sporadic and Familial Amyotrophic Lateral Sclerosis

TLDR

Intracellular protein aggregates in motor neurons, often containing Cu,Zn-superoxide dismutase (SOD1), are a hallmark of both sporadic and familial amyotrophic lateral sclerosis and are implicated in disease pathology. The study aimed to determine whether a shared aggregation pathway exists for familial ALS mutant SODs and wild‑type SOD1. Oxidative damage of both mutant and wild‑type SOD1 destabilizes the enzyme, induces monomer dissociation with minimal structural change, and promotes aggregation, revealing a common aggregation‑prone monomeric intermediate that links sporadic and familial ALS.

Abstract

Proteinacious intracellular aggregates in motor neurons are a key feature of both sporadic and familial amyotrophic lateral sclerosis (ALS). These inclusion bodies are often immunoreactive for Cu,Zn-superoxide dismutase (SOD1) and are implicated in the pathology of ALS. On the basis of this and a similar clinical presentation of symptoms in the familial (fALS) and sporadic forms of ALS, we sought to investigate the possibility that there exists a common disease-related aggregation pathway for fALS-associated mutant SODs and wild type SOD1. We have previously shown that oxidation of fALS-associated mutant SODs produces aggregates that have the same morphological, structural, and tinctorial features as those found in SOD1 inclusion bodies in ALS. Here, we show that oxidative damage of wild type SOD at physiological concentrations (∼40 μm) results in destabilization and aggregation <i>in vitro</i>. Oxidation of either mutant or wild type SOD1 causes the enzyme to dissociate to monomers prior to aggregation. Only small changes in secondary and tertiary structure are associated with monomer formation. These results indicate a common aggregation prone monomeric intermediate for wild type and fALS-associated mutant SODs and provides a link between sporadic and familial ALS.