Large SOD1 Aggregates May Be Protective, ALS Scientists Say

Toxicity, revealed? Trimeric SOD1 G147P complexes contributed to toxicity. But large SOD1 N53I aggregates helped protect motor neuron-like (NSC-34) cells, potentially by preventing trimer formation. [T = trimer; L = large aggregates. Courtesy of Zhu et al., 2018, Proceedings of the National Academy of Sciences.]

Researchers may be one step closer to identifying the source of motor neuron toxicity in SOD1 ALS. The study, led by University of North Carolina’s Nikolay Dokholyan in Chapel Hill, found that complexes containing just three molecules of the SOD1 enzyme promoted neurodegeneration – at least in cell culture. No signs of increased toxicity could be detected upon the introduction of large aggregates.

What’s more, these insoluble clumps, known as fibrils, reduced the loss of these motor neuron-like NSC-34 cells by about 50%, suggesting that these inclusions may instead protect these cells against the disease.

The findings build in part, on previous studies, which found that soluble SOD1 complexes accumulate in the spinal cord – at least in mouse models of the disease (Zetterstrom et al., 2007).

Together, the findings suggest that small, soluble oligomers of the misfolded enzyme may contribute to neurotoxicity in SOD1 ALS.

The study appeared on April 16 in the Proceedings of the National Academy of Sciences.

Meanwhile, scientists at the University of California-Los Angeles are capturing snapshots of these small complexes in hopes to develop treatments for SOD1 ALS that neutralize its potential toxicity (see Sangwan et al., 2017). The approach, based on “rational” drug design, is currently being used to create potential therapies that aim to protect motor neurons against SOD1 ALS by helping the enzyme fold properly (see May 2018 news). Stay tuned.

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To learn about other approaches being developed for SOD1 ALS, check out A New Potential ALS Gene Therapy Delivers A Key Milestone.

Featured Papers

Zhu C, Beck MV, Griffith JD, Deshmukh M, Dokholyan NV. Large SOD1 aggregates, unlike trimeric SOD1, do not impact cell viability in a model of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2018 Apr 16. [PubMed].

Sangwan S, Zhao A, Adams KL, Jayson CK, Sawaya MR, Guenther EL, Pan AC, Ngo J, Moore DM, Soriaga AB, Do TD, Goldschmidt L, Nelson R, Bowers MT, Koehler CM, Shaw DE, Novitch BG, Eisenberg DS. Atomic structure of a toxic, oligomeric segment of SOD1 linked to amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci U S A. 2017 Aug 15;114(33):8770-8775. [PubMed].

References

Zetterström P, et al. (2007) Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models. Proc Natl Acad Sci USA 104:14157–14162. [PubMed].

aggregates antisense oligonucleotides ASO ataxin-2 disease-als fibril inclusion misfolded SOD1 oligomer SOD1 topic-preclinical
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