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SOD1 Aggregates Identified in Brains of Patients with Parkinson's Disease



ARTICLE IN BRIEF

Researchers reported new evidence that superoxide dismutase 1 aggregates were associated with Parkinson's disease pathology.

BERLIN — What began as an effort to determine what makes cells in the substantia nigra vulnerable in Parkinson's disease (PD) ultimately led an international team of investigators to identify superoxide dismutase-1 (SOD1) aggregates in post-mortem tissue from people with this PD.

As the aggregates are common in degenerating motor neurons in amyotrophic lateral sclerosis (ALS), and concentrate is only the degenerating regions of the PD brain, the scientists said they suspect the abnormal protein might also play a role in brain cell death in PD.

Ben Trist, a graduate student at the Brain and Mind Centre and Discipline of Biomedical Sciences at the University of Sydney in Australia, reported the findings here in June at the International Congress of Movement Disorders and Parkinson's Disease.

Kay Double, PhD, associate professor at the University of Sydney and lead researcher on this work, told Neurology Today that this discovery began when she was studying dopamine-producing cells of the substantia nigra. “

They contain a melanin pigment and melanin binds metals,” she explained. “There was an increase in iron and a decrease in copper levels specifically within the degenerating brain regions in PD, and this change in copper led us to consider that SOD1 might be involved.”

SOD1 is a key antioxidant in the brain, and low levels of copper can alter the functioning of SOD1.

She and her colleagues found SOD1 in neurons in the substantia nigra. They found normal SOD1 in soluble form, but antibody staining revealed the presence of aggregated SOD1.

“That raised a red flag,” she said. She knew that the pathways that lead to SOD1 aggregation result in the death of motor neurons in the spinal cord in ALS patients with an SOD1 mutation. “Abnormal SOD1 also plays a role in sporadic cases of ALS,” she said.

Others had also reported that some patients with PD have a loss of motor neurons in the spinal cord, while some ALS patients lose cells in the substantia nigra.”

Working with colleagues at the Florey Institute of Neuroscience and Mental Health in Melbourne and at the University of Bordeaux in France, the scientists conducted studies to characterize the aggregates and to count their distribution throughout the PD brains and those of normal controls.

Using immunohistochemistry, they identified Lewy body pathology and SOD1-immunopositive protein aggregates in regions of significant neuronal loss in the PD brain, said Dr. Double.

“The SOD1 protein aggregate was significantly more abundant in degenerating regions of the PD brain (with more than a five-fold increase in substantia nigra, and more than 2.5-fold increase in the locus coeruleus) compared with non-degenerating PD brain regions or in control brains.

Like SOD1 pathology in ALS, these aggregates contained significant amounts of SOD1, copper chaperone for SOD1 and ubiquitin, but not alpha-synuclein. A positive isoelectric point shift in SOD1 was also observed in the PD, compared with control brain, the researchers said.

“No one had ever looked for SOD1 aggregates in PD. It just slipped under the radar,” Dr. Double told Neurology Today. “We looked at the amount of SOD1 and the functioning of the protein. The enzymatic activity of the protein is reduced. One of the reasons that SOD1 aggregates in ALS is because it is not binding copper.”

Dr. Double said she suspects that the SOD1 pathology could have a role in the vulnerability of the substantia nigra in PD. “We have found a 60 percent loss of copper in neurons in the substantia nigra in PD, so it makes sense that part of the problem with SOD1 in PD is that it is not binding adequate amounts of copper to enable the enzyme to function normally.”

The researchers also had access to two brains from people with a pathological form of preclinical PD but no clinical disease. An intermediate number of SOD1 aggregates were found in these brains, suggesting that the formation of the aggregates occurs very early in the disease process.

If the pathology is similar to what is seen in ALS, Dr. Double said, it is possible that the two diseases could respond to the same treatment.

Figure

DR. KAY DOUBLE: “No one had ever looked for SOD1 aggregates in PD. It just slipped under the radar.”

EXPERTS WEIGH IN

ALS researcher Jeffrey Rothstein, MD, professor of neurology and neuroscience and director of the Brain Science Institute at Johns Hopkins University, said that when aggregates form, they can trap lots of other cytosolic protein in them. Since SOD1 is a very highly abundant cytosolic protein — 1 percent of all body protein is SOD1 — its not surprising that it could “decorate” these inclusions.”

Dr. Rothstein agrees that the finding of the aggregates call for “additional experiments aimed at reducing SOD1 to see if it has any meaningful pathophysiological changes.”

“This is extremely interesting,” said Robert H. Brown, Jr., MD, PhD, chair of the department of neurology at UMass Medical School. “There is a growing and credible body of data documenting misfolding of non-mutant SOD1 in ALS, typically demonstrated using antibodies specific for misfolded SOD1. These studies suggest the hypothesis that SOD1 may represent a convergence point in ALS, driving pathology by misfolding even if not mutated. Further, these reports have been used to support the view that both wild type and mutant SOD1 can adopt a prion-like behavior, self-assembling to form toxic aggregates that can propagate more misfolding.

“What I have not seen extensively studied yet is misfolding of SOD1 in other neurodegenerative disorders. This study would appear to show that misfolding of wild-type SOD1 is not specific. And, if it is not specific to ALS one might envision two opposite extremes of interpretation (and there are probably many others).

“Perhaps misfolding of wild-type SOD1 is neurotoxic and drives pathogenesis in many neurodegenerative diseases, linking ALS, PD and perhaps other disorders as a common, disease-triggering, miscreant protein. At the other end of the spectrum, does this study suggest that misfolding of wild-type SOD1 is simply a byproduct pathology in a dying neuron, which is completely unrelated to causing disease?”

David Sulzer, MD, professor of psychiatry, neurology and pharmacology at Columbia University Medical Center, agrees with this idea. “When you begin to aggregate one type of protein, the same type of aggregation may occur with other proteins. Maybe there is a convergence in these processes that lead to aggregation in neurodegenerative disorders.”

“There seems to be a serious problem with copper dysregulation in the affected region in PD,” said Ashley Bush, MD, PhD, professor of neuroscience at the Florey Institute for Neuroscience and Mental Health at the University of Melbourne, who has spent his career studying the role of metals in neurodegenerative diseases.

“We have looked at this too. We found that this may contribute to lowered nigral ceruloplasmin activity, which, in turn, can cause toxic iron accumulation. It's a domino effect.”

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•. International Congress of Parkinson's Disease and Movement Disorders Abstract 743: Trist BG, Davies KM, Genoud S, et al. SOD1 aggregation: A pathological link between Parkinson's disease and amyotrophic lateral sclerosis http://www.mdsabstracts.org/abstract/sod1-aggregation-a-pathological-link-between-parkinsons-disease-and-amyotrophic-lateral-sclerosis/.
    •. Ayton S., Lei P, Duce JA, et al. Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease http://onlinelibrary.wiley.com/doi/10.1002/ana.23817/full. Ann Neurol 2013; 73:554–559.
      •. Ayton S., Lei P, Adlard PA, et al. Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson's disease https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/1750-1326-9-27. Mol Neurodegener 2014; 9:27.