ALS is a disease characterized by death of motor neurons and loss of motor function. There are two types of ALS; familial and sporadic, with sporadic ALS accounting for 90-95% of ALS cases. The familial form is associated with a heritable mutation in a number of genes such as superoxide dismutase 1, c9orf72, and many more. Copper-Zinc Superoxide dismutase 1 (Cu-Zn SOD-1) is a dimetallated antioxidant protein found in all cells and is responsible for converting harmful oxygen radicals, which are produced naturally and can cause widespread cellular damage, into hydrogen peroxide. In some mutants of SOD-1, there can be misfolding of the protein, aggregation of mutant proteins, or inability to coordinate metal ions, all leading to loss of function and can contribute to progression of ALS. Notably, mutations in SOD-1 differentially impact motor neurons, causing their degeneration but not death in other cell types. Recently, it was hypothesized that a particular mutant of SOD-1 actually reverses its job and generates reactive oxygen species, the opposite of its normal function. The mutant H43R, which has the capability of denaturing at physiological temperatures, was shown to exhibit increased pro-oxidant activity in the empty form and the copper-bound form. It also was found that in an environment mimicking that within a cell, the pro-oxidant activity was even higher and the copper-bound protein was likely stabilized. These findings give rise to a possible mechanism by which the SOD-1 mutant contributes to oxidative stress within the cell and could result in the degeneration observed in ALS.
Chise Nagao, Kunisato Kuroi, Taiyu Wakabayashi, Takakazu Nakabayashi. Molecules 2020, 25(16), 3600; https://doi.org/10.3390/molecules25163600