Researchers
reported new evidence that superoxide dismutase 1 aggregates were associated
with Parkinson's disease pathology.
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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.
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.”
doi:
10.1097/01.NT.0000490354.26741.b3
http://journals.lww.com/neurotodayonline/Fulltext/2016/07210/News_from_the_International_Congress_of.9.aspx
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