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AMERICAN ACADEMY OF NEUROLOGY
Is Parkinson’s Disease a Prion Disorder?
2013;21(5):1, 34.
SAN DIEGO—An increasing body of evidence suggests that Parkinson’s
disease is a prion disorder, according to a review presented at the 65th Annual
Meeting of the American Academy of Neurology. If the prion hypothesis is
confirmed, it could lead to the pursuit of novel therapeutic targets.
Developing new medical treatments will still require “an enormous amount of
work,” said C. Warren Olanow, MD, Professor of Neurology and Neuroscience
at the Mount Sinai School of Medicine in New York City. “Many compounds will
have to be tested in high-throughput studies to find lead compounds that
interfere with the prion process, but this approach currently offers the best hope
for finding a cure for Parkinson’s disease.”
Alpha Synuclein May Be a Prion
A prion is an infectious agent made solely of misfolded protein. The most
common illness caused by prions in humans is Creutzfeldt–Jakob disease.
Parkinson’s disease may occur when native alpha synuclein, which normally
exists in an alpha helical configuration, misfolds and forms beta sheets.
Misfolding can result from an alpha synuclein gene mutation, excess production
of or damage to alpha synuclein, or random chance, said Dr. Olanow. Normally,
lysosomes or proteasomes clear the misfolded alpha synuclein. If it is not
cleared, the protein can form aggregates that further interfere with lysosomal
and proteasomal function. Misfolded alpha synuclein can promote the
misfolding of wild-type alpha synuclein, and lead to the formation of toxic
oligomers and aggregates that cause neurodegeneration.
“The significance of the Lewy body is not known, but it may represent a
protective mechanism that forms in an attempt to clear and segregate misfolded
protein aggregates,” said Dr. Olanow. “Furthermore, recent evidence
demonstrates that misfolded alpha synuclein protein filaments and aggregates
can transfer to unaffected cells to extend the disease process.”
Research Has Supported the Prion Hypothesis
The link between Parkinson’s disease and protein aggregates was established
about 100 years ago when Lewy bodies were identified as a characteristic
pathologic feature of the illness, said Dr. Olanow. In 1997, a mutation in the
alpha synuclein gene was found to be responsible for some cases of
Parkinson’s disease. Mutant alpha synuclein is more likely to misfold than wildtype alpha synuclein. Researchers subsequently demonstrated that alpha
synuclein is the principal protein in Lewy bodies and Lewy neurites. Duplication
or triplication of the alpha synuclein gene was found to cause a form of
Parkinson’s disease, which indicated that overexpression of the normal protein
itself could cause the disease.
Alpha synuclein staining in elderly controls and patients with Parkinson’s
disease suggested that the earliest CNS changes in Parkinson’s disease occur
in the dorsal motor nucleus of the vagus nerve and in the olfactory system.
These regions’ proximity to the external environment suggested that exposure
to toxins or infectious agents could initiate the disease process, which could
then spread to other parts of the nervous system in a prion-like manner.
More recently, Dr. Olanow and colleagues examined transplanted fetal nigral
neurons that had been implanted into patients with Parkinson’s disease 10 to 14
years previously. The implanted neurons showed evidence of Lewy pathology,
which supported the possibility that Lewy pathology had extended from affected
to unaffected neurons in a prion-like manner.
In 2012, Virginia Lee and colleagues injected synthetic alpha synuclein fibrils
into the striatum of wild-type mice. This intervention was associated with the
development of Lewy pathology and neurodegeneration in neighboring neurons
with spread to the cortex and the olfactory bulb, as well as the substantia nigra
and the contralateral cortex.
Prion Hypothesis Could Yield Novel Therapeutic Targets
Confirmation that Parkinson’s disease is a prion disorder would suggest novel
targets for candidate neuroprotective therapies. Such approaches could include
agents that prevent protein misfolding, immunization to remove toxic oligomers,
and downregulation of native alpha synuclein to prevent its participation in prion
reactions, said Dr. Olanow.
Studies are now beginning to test methods for removing toxic fibrils and
aggregates through vaccination techniques. “But we don’t know yet for sure
which component is toxic,” said Dr. Olanow, “and it is possible that we could be
removing protective aggregates that could accelerate the disease process.”
Attempting to inhibit the prion conformer reaction could be a more promising
approach, according to Dr. Olanow. If misfolded alpha synuclein causes native
alpha synuclein to misfold through molecular mechanisms, these mechanisms
“could be targets for a therapeutic intervention,” he added.
The best approach might be to eliminate native alpha synuclein entirely so that
none of it could become misfolded. The approach could allow clearance
systems to remove remaining misfolded alpha synuclein, potentially stopping
the chain reaction of misfolding. “In experimental systems, knockout of alpha
synuclein might remove substrate and slow down or stop the prion process,”
said Dr. Olanow. “The prion concept is extremely exciting and hopefully will lead
to an effective therapy.”
—Erik Greb
Senior Associate Editor
Suggested Reading
Bae EJ, Lee HJ, Rockenstein E, et al. Antibody-aided clearance of extracellular
a-synuclein prevents cell-to-cell aggregate transmission. J Neurosci.
2012;32(39):13454-13469.
Luk KC, Kehm V, Carroll J, et al. Pathological a-synuclein transmission initiates
Parkinson-like neurodegeneration in nontransgenic mice. Science.
2012;338(6109):949-953.
Olanow CW, Brundin P. Parkinson’s disease and alpha synuclein: is
Parkinson’s disease a prion-like disorder? Mov Disord. 2013;28(1):31-40.