Since the discovery of Superoxide Dismutase I (SOD1) mutations in 1993 as cause of ALS, many hypothesis has been formulated about the mechanisms by which they lead to motor neurons death.

Protein aggregation is a hallmark of neurodegenerative disease and protein aggregates are found in post-mortem motor neurons from patients and in models. SOD1 aggregates have been studied for many years speculating about their direct involvement in cell toxicity. Moreover it is still unclear whether and how protein aggregates may play a central role in ALS onset and progression.

A recent study published in the December on Proceedings of the National Academy of Sciences online demonstrated that a small aggregate of SOD1 protein, trimeric SOD, is toxic to motor neurons, and mutations that stabilize the trimeric form are more toxic than ones that destabilize it, providing a direct link between aggregate presence and neuron death.

As the author report in the article "Recognizing and sequestering SOD1 trimer or preventing its formation is a potential strategy for preventing neurodegeneration" as has been done in other neurodegenerative diseases, i.e. Alzheimer's disease. The findings provided bring important contributions to disease knowledge and open new perspective for ALS drug discovery; as they conclude "The characterization of structural features, such as the identification of nonnative aggregation interfaces in this work, provides a key step in the understanding of ALS disease etiology and development of therapeutic or preventive strategies".

Reference:

Proctor EA, Fee L, Tao Y, Redler RL, Fay JM, Zhang Y, Lv Z, Mercer IP, Deshmukh M, Lyubchenko YL, Dokholyan NV. Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis. PNAS 2016 Jan 19;113(3):614-9.[Pubmed].