Mechanism Slows Parkinson's in Mice
October 24, 2001; 17:00 EST -- An unanticipated development in Parkinson's disease research, reported today, is likely to fuel yet more speculation about the actual role of protein aggregates in neurodegenerative disease. Neuroscientist Eliezer Masliah and his team at the University of California San Diego report that a previously unknown endogenous mechanism inhibits self-aggregation of a protein implicated in Parkinson's Disease.
This provides a new target to test the hypothesis that protein aggregates play a causative role in such disorders. "It also could have therapeutic implications," says Masliah, who is Professor of Neurosciences and Pathology.
In the last few years, protein aggregation has emerged as the hallmark of several neurodegenerative disorders including Alzheimer's disease (AD), PD, Huntington's Disease, Amyotrophic Lateral Sclerosis, and the prion diseases. Scientists remain divided on the role of aggregation in causing disease but the new evidence suggests "there is a natural balance between proteins tending to aggregate and proteins tending to prevent [aggregation]," Masliah told BioMedNet News.
PD and related neurodegenerative disorders are characterized by Lewy Bodies, abnormal occlusions in the cytoplsma of neurons. The alpha-synuclein protein is the most abundant component of Lewy Bodies and mutations in the gene are associated with rare familial forms of Early-Onset PD.
Although initially identified as the non-amyloid component in AD, alpha-synuclein, like beta-amyloid, has been shown to self-aggregate to form fibrils. The protein has two homologs, beta- and gamma-synuclein, but has no known function.
Masliah and his colleagues now report that beta-synuclein inhibits self-aggregation of alpha-synuclein and, in PD mice, reverses motor and chemical deficits. The results are published tomorrow in Neuron.
Since publication of the results, Masliah has been investigating the possibility of gene therapy with beta-synuclein and suggests the protein may be a therapeutic target for PD. The researchers have also identified a region of the protein that is critical to its activity, and "are now trying to find chemical analogs," Masliah says.
The results provoke a topic of much debate among neuroscientists. Several researchers have suggested that protein aggregates do not cause the disease, and instead represent a compensatory mechanism to protect the cell from disease. "That's the million-dollar question," said Julie Andersen, Associate Professor at the Buck Institute for Aging Research. "It is not yet clear whether the aggregates are causative, whether it's compensatory or protective, or if it's just correlative." Given such uncertainty, Andersen says, "a therapeutic approach that removes aggregates may be premature and may even be harmful."
"That's a very important, really critical question," agreed Masliah, adding he too suspects large aggregates or fibrils may have a protective function. He elaborates on an emerging hypothesis in neurodegenerative disorders: Small aggregates, or oligomers, are the causative agent in the disease, while large aggregates, or polymers, are ultimately beneficial.
"While dismantling large polymers could create many oligomers and exacerbate the disease, it would require potent proteases to break apart the fibrils," Masliah says, adding that "beta-synuclein is simply not up to the task. Rather, beta-synuclein probably targets smaller oligomers that have diffusible, toxic components, thus preventing disease progression," he suggests.
"There are also some issues with the model that they've used," Andersen told BioMedNet News . For example, the model does not exhibit certain phenotypic characteristics of the disease, such as the cellular location of occlusions. Beta-synuclein transgenics also seem to fare better that wildtype mice, suggesting "there may be something going on beyond just beta inhibiting alpha." Still, "given the caveat that the animals are not perfect," Andersen said, "it's a very intriguing idea that beta-synuclein could be acting as a natural inhibitor of alpha-synuclein."
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