The threat of instability: neurodegeneration predicted by protein destabilization and aggregation propensity

Abstract

A new method based on protein stability and aggregation propensity reveals a strong correlation between the properties of mutant Cu/Zn-superoxide dismutases associated with amyotrophic lateral sclerosis and patient survival.

Figure 1. Misfolding and Aggregation of SOD1

Wang et al.'s correlation of mutant SOD1 properties with disease duration [6] implicates two steps in the formation of aggregates of SOD1 in ALS: (1) native homodimeric metalloprotein, shown in ribbon representation (left) partially or completely unfolds to form a range of possible dimeric or monomeric aggregation-prone species, shown as a general grey irregular shape (middle), followed by (2) progressive assembly of the aggregation-prone species to form initially small soluble and later fibrillar aggregates (right panels). The structure of native SOD1 was generated using MolMol [29] and Protein Data Bank accession code 1n18. Sites of ALS-associated mutations studied by Wang et al. are shown in red; bound copper and zinc ions are shown as blue and black spheres, respectively. The right panels are transmission electron microscopy images of apo SOD1 aggregates formed in vitro that strongly resemble granular and granule-coated fibrillar SOD1 aggregates observed in ALS [19].