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Over-oxidized Form of Superoxide Dismutase in Sporadic Bulbar ALS Shares Toxic Mechanism with Mutant SOD1

March 20, 2012
Piera
Piera Pasinelli, Ph.D.

A recent study published in the Proceedings of the National Academy of Sciences (PNAS) explored the role of Cu/Zn Superoxide Dismutase 1 (SOD1) found in sporadic ALS with bulbar onset.  The team led by ALS Association-funded investigator Piera Pasinelli, Ph.D., Thomas Jefferson University, Pennsylvania, asked whether post-translational modifications to SOD1 could lead to disease in sporadic ALS cases.

“This is an extremely important question to answer as it has implications for treatment approaches currently aimed only at 2 % of ALS cases linked to SOD1 mutations, and may also have benefit for other cases of ALS,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D.

Analysis of SOD1 isolated from patient-derived lymphoblasts – immature cells which typically change to form mature lymphocytes (white blood cells) – from a subset of bulbar onset patients by a technique called “immunoprecipitation” identified iper-oxidized SOD1, which is above baseline oxidation levels.  Interestingly this was seen in seven cases of bulbar ALS not seen in four cases of familial ALS or 13 cases of lower and upper limb onset.  Ten healthy controls were also included in the analysis.  Similar to mutant SOD1-like properties, iper-oxidized SOD1 isolated from sporadic bulbar onset cases formed a toxic complex with mitochondrial Bcl 2, when further stressed.

There was no correlation between the appearance of the iper-oxidized SOD1 and patient’s sex, age, or duration or progression of disease.  However, it did correlate with bulbar onset, highlighting that the underlying mechanism in various subsets of ALS may differ and, with further validation of levels of iper-oxidation, may provide a biomarker to define various subsets of ALS as well as have therapeutic implications.

“This is the first time that it is shown in patient derived cells that SOD1 is a target and a marker of disease in sporadic ALS,” said Dr. Pasinelli.  “Rather than a misfolded and unstable SOD1, it is an over-oxidized SOD1 that pre-disposes the cells to an age-or-environmental stress that ultimately trigger disease.”

This new study was supported by The ALS Association with funds from its Greater Philadelphia Chapter.  Visit http://www.pnas.org/content/early/2012/03/09/1115402109.long to read the full report in PNAS.

Previous studies suggest that misfolded SOD1 may not only be a cause of familial cases of ALS linked to SOD1 mutations but also a cause of sporadic ALS cases.  In an August 2011 report, investigators led by Brian K. Kaspar, Ph.D., Ohio State University School of Medicine, concluded that astrocytes isolated from post-mortem cases of ALS resulted in motor neuron damage; furthermore, the damage could be reversed by lowering SOD1 in these astrocytes.  To read about this study, visit http://www.alsa.org/news/archive/astrocytes-toxic-to-neurons.html.

Dr. Pasinelli continued, “We, of course, need to confirm our data using a large cohort of patients, but we are glad to see that the presence of an over-oxidized SOD1 seems to correlate with bulbar onset, leading to the possibility to sub-classify sporadic ALS based on specific biomarkers.”

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