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bioRxiv · 10.1101/2020.07.13.199976

Insight into the autosomal-dominant inheritance pattern of SOD1-associated ALS from native mass spectrometry

cveticanin, j.·Mondal, T.·Meiering, E. M.·Sharon, M.·Horovitz, A.
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Abstract

About 20% of all familial amyotrophic lateral sclerosis (ALS) cases are associated with mutations in superoxide dismutase (SOD1), a homodimeric protein. The disease has an autosomal-dominant inheritance pattern. It is, therefore, important to determine whether wild-type and mutant SOD1 subunits self-associate randomly or preferentially. A measure for the extent of bias in subunit association is the coupling constant determined in a double-mutant cycle type analysis. Here, cell lysates containing co-expressed wild-type and mutant SOD1 subunits were analyzed by native mass spectrometry to determine these coupling constants. Strikingly, we find a linear positive correlation between the coupling constant and the duration of the disease. Our results indicate that inter-subunit communication and a preference for heterodimerization greatly increase the disease severity.

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cveticanin, j., Mondal, T., Meiering, E. M., Sharon, M., Horovitz, A.. 2020-07-13. Insight into the autosomal-dominant inheritance pattern of SOD1-associated ALS from native mass spectrometry. https://doi.org/10.1101/2020.07.13.199976

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