Mutation-dependent Polymorphism of Cu,Zn-Superoxide Dismutase Aggregates in the Familial Form of Amyotrophic Lateral Sclerosis

Yoshiaki Furukawa,Kumi Kaneko,Koji Yamanaka,Nobuyuki Nukina

doi:10.1074/jbc.m110.113597

Yoshiaki Furukawa, Kumi Kaneko + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m110.113597

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Abstract

More than 100 different mutations in Cu,Zn-superoxide dismutase (SOD1) are linked to a familial form of amyotrophic lateral sclerosis (fALS). Pathogenic mutations facilitate fibrillar aggregation of SOD1, upon which significant structural changes of SOD1 have been assumed; in general, however, a structure of protein aggregate remains obscure. Here, we have identified a protease-resistant core in wild-type as well as fALS-causing mutant SOD1 aggregates. Three different regions within an SOD1 sequence are found as building blocks for the formation of an aggregate core, and fALS-causing mutations modulate interactions among these three regions to form a distinct core, namely SOD1 aggregates exhibit mutation-dependent structural polymorphism, which further regulates biochemical properties of aggregates such as solubility. Based upon these results, we propose a new pathomechanism of fALS in which mutation-dependent structural polymorphism of SOD1 aggregates can affect disease phenotypes.

Highlights

Misfolding of a protein molecule often causes its insoluble aggregation, and formation of inclusion bodies containing protein aggregates is a major pathological change in conformational diseases such as neurodegenerative disorders [1]
We propose a new pathomechanism of form of amyotrophic lateral sclerosis (fALS) in which mutationdependent structural polymorphism of SOD1 aggregates can affect disease phenotypes
Given that aggregate polymorphism associates with different disease phenotypes in the other neurodegenerative disorders such as prion diseases [2, 3], an assumption on a “mutation-independent” structure of SOD1 aggregates should be carefully examined; phenotypic heterogeneity has been reported in fALS patients with different SOD1 mutations [19]

Summary

Introduction

Misfolding of a protein molecule often causes its insoluble aggregation, and formation of inclusion bodies containing protein aggregates is a major pathological change in conformational diseases such as neurodegenerative disorders [1]. We have revealed that non-native interactions among regions A–C form a core structure of SOD1 fibrillar aggregates.

Results

Conclusion