Conference Coverage

Is Parkinson’s Disease a Prion Disorder?


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 wild-type 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.”


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