The viability of cells containing mutant SOD1 that strongly
forms larger fibrils, but decreased amounts of trimers tended to be similar to the
wild-type SOD1, suggesting that
‘Inhibition of trimer formation or promoting formation of larger aggregates of SOD1 protein may reduce nerve cell damage in amyotrophic lateral sclerosis (ALS).’
Thus, the findings of the study suggest that SOD1 fibrils
may not be the problem in SOD1-linked ALS; rather, they might be a solution
Normal SOD1 Protein
versus Abnormal Trimeric Form
- The normal form of SOD1 protein
exists as a dimer or two copy structure. Abnormal toxic trimers form when
the dimers disintegrate.
scientists are looking to develop an agent that can stabilize the dimeric form of the
protein, while limiting the formation of toxic trimers
or other oligomers
"Taking a drug to promote fibril formation could be one
(another) way to reduce toxicity in SOD1-ALS," Dokholyan said.
Indeed future plans in Dokholyan's lab are to further
delineate cellular mechanisms of toxicity due to pathological SOD1 trimers and
find drugs that reduce the formation of trimers.
About SOD1 Mutant Protein
SOD1 gene mutation occurs in a significant proportion of ALS
cases, accounting for about 12 percent of ALS cases that tend to run in
families. SOD1 mutations also occur in approximately 1.5 percent of ALS cases
that do not obviously run in families. All these mutations destabilize the
protein's normal (dimeric) structure and promote formation abnormal aggregates
of the SOD1 protein with resultant pathology.
findings of the study provide an insight into the possible reasons for nerve
cell damage in
diseases and may fuel further research and aid in the development of novel
drugs that target the toxic abnormal trimeric form of SOD1 protein.
"Although SOD1-associated ALS represents a small
fraction of all ALS cases, uncovering the origins of neurotoxicity in SOD1
aggregation may shed light on the underlying causes of an entire class of
neurodegenerative diseases," Dokholyan said.
- Cheng Zhu el al., "Large SOD1 aggregates, unlike trimeric SOD1, do not impact cell viability in a model of amyotrophic lateral sclerosis," PNAS (2018). http://www.pnas.org/cgi/doi/10.1073/pnas.1800187115