Larger Clusters of ALS Protein Can Protect Brain Cells

Larger Clusters of ALS Protein Can Protect Brain Cells

by Dr. Lakshmi Venkataraman on Apr 17 2018 5:28 PM
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  • 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.


Aim of Study

  • 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 trials.
  • 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 trimers on the nerve cells in ALS.


Details of Study

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 Study

  • When the test cells expressed SOD1 mutants predominantly forming trimers, the neurons died much more quickly than control cells expressing normal SOD1 protein.
  • The trimer-expressing cells even died more quickly than cells expressing other mutant forms of SOD1 protein similar to those found in severe hereditary ALS cases.
"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.

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.
The 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 (small molecules).

"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 Associated ALS

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.


The findings of the study provide an insight into the possible reasons for nerve cell damage in

neurodegenerative 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.

  1. Cheng Zhu el al., "Large SOD1 aggregates, unlike trimeric SOD1, do not impact cell viability in a model of amyotrophic lateral sclerosis," PNAS (2018).