- Small aggregates
(trimers) rather than larger aggregates of abnormal SOD1 protein found to
be highly toxic to nerve cells resulting in their damage and death in
amyotrophic lateral sclerosis (ALS).
- ALS or Lou Gehrig's disease is a
rare but progressive neurological condition marked by damage to nerve
cells in brain and spinal cord causing difficulty of voluntary muscle
activity such as walking, talking and chewing.
Small aggregates (trimers) of mutated SOD1 protein shown to
be highly toxic while larger aggregates may have a protective effect on neurons
(nerve cells) according to a recent study conducted by scientists at the
University of North Carolina (UNC) School of Medicine at Chapel Hill. The
findings of the study appear in the Proceedings of the
National Academy of Sciences.
- Many neurodegenerative diseases such
as Alzheimer's disease ALS,
Parkinson's disease and Huntington's disease are characterized by
formation of large protein aggregates within nerve cells.
- Several drug treatments have been
developed to target and eliminate these larger abnormal protein clusters
but they have been found to be ineffective in several clinical
- Additionally, there is no evidence to show
that these large protein aggregates are harmful to nerve cells; on the
other hand, earlier studies have shown that "trimer"
structures made of just three copies of the SOD1 protein are toxic and
cause injury and death to neurons in ALS.
Therefore, the current study was aimed at studying and
comparing the effects of large protein aggregates and the smaller aggregates or
on the nerve cells in ALS.
The study was conducted by a team of scientists including
senior author Nikolay Dokholyan, PhD, the Michael Hooker Distinguished
Professor of Biochemistry and Biophysics at UNC-Chapel Hill and lead author
Cheng Zhu, PhD, a postdoctoral researcher in his lab.
- The team found a mutation
that stabilizes the protein aggregates in the trimeric form, which
normally occurs only transiently, thereby enabling its analysis.
"One challenge is that the smaller structures such as
trimers tend to exist only transiently on the way to forming larger
structures," Zhu said. "But we were able to find an SOD1 mutation
that stabilizes the trimer structure and another mutation that promotes the
creation of the larger fibrils
at the expense of smaller structures. So, we
were able to separate the effects of these two species of the protein."
- The team also successfully expressed
mutant forms of the SOD1 protein (not necessarily trimers) in test cells
that closely resembled neurons affected in ALS.
Key Observations of
- When the test
cells expressed SOD1 mutants predominantly forming trimers, the neurons
died much more quickly than control cells expressing normal SOD1 protein.
trimer-expressing cells even died more quickly than cells expressing other
mutant forms of SOD1 protein similar to those found in severe hereditary
"Looking at various SOD1 mutants, we
observed that the degree of (nerve cell) toxicity correlated with the extent of
trimer formation," Zhu said.
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 fibrils formation may be protective as well,
and not just less toxic
‘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