MIAMI BEACH — Aggregation of proteins within dopaminergic and other neuronal cells may play an important role in the development and progression of Parkinson's disease.

Although the etiology of Parkinson's disease is likely multifactorial, these findings point researchers toward one important group of candidate targets for future therapies, Dr. C. Warren Olanow said at the World Federation of Neurology World Congress on Parkinson's Disease and Related Disorders.

“Although we have not yet found a neuroprotective drug for Parkinson's disease, the future is looking brighter,” he said. “Gene studies are directing us to look at mitochondria and proteins that lead to misfolding and prion-like activity. This may lead to very promising therapies.”

Dr. Olanow is chairman emeritus of the department of neurology at Mount Sinai School of Medicine, New York. He disclosed that he is a consultant for Boehringer Ingelheim GmbH, Ceregene Inc., Merck Serono S.A., Novartis Pharmaceuticals Corp., and Teva Neuroscience Inc., all of which manufacture or are developing medications for Parkinson's disease.

Normally, there is a balance between the number of proteins being formed and the ability to clear them, said Dr. Olanow. “Protein aggregation is much more than what we appreciated. Of the systems for clearing accumulated protein, the ubiquitin-proteasome system is the most important. This is a series of enzymes that signal for protein to be transported to a proteasome, where it is broken down.”

Healthy embryonic cells transferred to the substantia nigra of a person with Parkinson's disease have shown characteristic features of the disease (Nat. Med. 2008;14:504-6). In that study, the transplants showed hallmark signs of Parkinson's disease, including Lewy body pathology; increased levels of the protein alpha-synuclein, a protein of unknown function found abundantly in Lewy bodies; and reduced amounts of dopamine transporter in a post mortem examination 14 years later. The grafted cells had adopted the features of the host dopaminergic neurons, suggesting that ongoing changes occur with Parkinson's disease.

Aggregation and misfolding may occur when excess protein overwhelms the clearance system and/or a neuron with normal levels has an impaired clearance system. Lysosomal or proteasomal degradation of alpha-synuclein is likely the clearance mechanism in healthy individuals. “Overproduction of alpha-synuclein alone is shown to be enough to start the cell death process in Parkinson's disease,” Dr. Olanow noted.

Although alpha-synuclein is a major focus of research, other proteins are likely involved in Parkinson's disease as well, Dr. Olanow said. “With respect to the lysosome system, as you increase protein accumulation, it begins to block the LAMP [lysosome-associated membrane protein] receptors and other proteins can start to accumulate as well.”

Neuron-to-neuron transmission of alpha-synuclein has been demonstrated (Proc. Natl. Acad. Sci. USA 2009;106:13010-15). In that study, a substantial number of transplanted healthy embryonic cells overexpressed alpha-synuclein from host cells in a relatively short time, Dr. Olanow said. “This showed that alpha-synuclein can travel across a neuron and be taken up by a healthy neuron, leading to protein uptake, aggregation, and cell death.” This endocytosis of alpha-synuclein from one neuron to another might play a role in the progressive spread of Lewy pathology in the nervous systems of people with Parkinson's disease.

“With that in mind, we can perhaps revise the hypothesized model [to say] that alpha-synuclein itself can act as a prion to promote protein accumulation,” said Dr. Olanow (Proc. Natl. Acad. Sci. USA 2009;106:12571-2).

“This could perhaps explain the fascinating observations suggested by Braak and his colleagues [Neurobiol. Aging. 2003;24:197-211] where [effects of the disease are] first seen in the olfactory bulb and the brain stem, then spread to other brain regions,” he said. “Could it be a prion-like effect?”

An attendee asked why some brain regions are not included in Braak's hypothesis about connections between different anatomic areas playing a role in progression of Parkinson's disease. “I don't know the answer,” Dr. Olanow said. “[This] is pure speculation, but one type of cell might have a better ability to clear proteins than another.”

The sobering news is that much about the pathogenesis of Parkinson's disease remains unknown. “We are not sure which factor, if any, is the primary driver of cell death. And the primary factor may be different in different individuals,” Dr. Olanow said. In addition, there may be a network of different, interactive pathogenic factors that initiate the disease process, “so blocking any one of them might not halt the process.”

Even so, these recent findings could lead to neuroprotective therapies directed at proteins and/or agents that prevent protein misfolding, promote refolding, and/or facilitate clearance of aggregated proteins, he said.

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Gene study data suggest looking at 'mitochondria and proteins that lead to misfolding and prion-like activity.'

Source DR. OLANOW

Protein Aggregation May Drive PD Development, Progression