It’s easy to distinguish a healthy person from a person with advanced Parkinson’s: the Parkinson’s sufferer has large clumps of proteins in his or her brain cells. Scientists disagree, however, about the nature of these clumps. Some contend that they lead to the massive neuronal cell death and resulting movement disorders in Parkinson’s, others that the clumps are merely a byproduct of the disease – and some scientists contend that the clumps are actually protective, sequestering toxic proteins so they can’t hurt the cell. Mounting evidence points to the last possibility.
Existing research already suggests that the biggest clumps, known as inclusions, are helpful. Cells that form clumps of the mutant Huntington protein, for example, survive longer than clump-free cells. Now MIT scientists have discovered a compound that increases clumps in cell models of Huntington’s and Parkinson’s disease and makes the cells healthier. Scientists aren’t sure how the compound works, but they think it might be helping cells get rid of toxic forms of the proteins floating around in the cell by isolating them into clumps.
“Using a compound to promote inclusions is a novel therapeutic approach,” says Ruth Bodner, an MIT neuroscientist who led the research.
Many neurodegenerative diseases are linked to misshapen proteins, which tend to stick together, aggregating into blobs of tens, hundreds, thousands, or more, which are eventually visible in diagnostic tests. These proteins disrupt cellular processes and eventually lead to cell death. Unfortunately, scientists don’t know exactly at what stage of aggregation the proteins are most harmful or how they kill cells.
In a large-scale drug screen published today in the Proceedings of the National Academy of Sciences, Bodner, MIT biology professor David Housman, and colleagues studied cells expressing mutant proteins implicated in Parkinson’s disease and Huntington’s disease. To their surprise, they identified a compound, called B2, which boosted the number of clumps as well as the health of the cells; Parkinson’s cells that normally would have died survived when given B2. And Huntington’s cells treated with the compound had better functioning proteosomes – cellular “garbage cans” that are often dysfunctional in the disease.
The findings could provide a novel approach to drug development. “If you develop a molecule that is truly targeting the cellular pathway by which cells recognize malformed proteins and try to deal with them, I think it could have broad implications,” says Steven Finkbeiner, a neurologist at the University of California, San Francisco. “A number of other neurodegenerative and non-neural diseases are characterized by abnormal proteins folding,” he adds.
Roger Barker, a neurologist at the University of Cambridge, U.K., thinks the findings are very intriguing. “This is a completely different approach to what people have done before,” he says. But he cautions that the results will need to be repeated in animal models before scientists can really get a sense of the therapeutic potential for these compounds. Housman and Bodner say they now plan to search for more potent versions of the compounds used in the study and to test them in animal models.
The researchers would also like to figure out how the B2 compound works. Cells usually get rid of misshapen proteins by breaking them down in proteosomes. But this mechanism may get overloaded in neurodegenerative disease. Housman and Bodner theorize that the compound works by helping the cell sequester into clumps the single proteins or smaller aggregates of proteins that might be harmful to the cell.
Most research has focused on trying to decrease protein aggregates, says Ole Isacson, a neuroscientist at McLean Hospital in Belmont MA, and Harvard Medical School in Boston. “This paper supports the idea that getting rid of [proteins]…is more important than getting rid of aggregates,” he says.
The researchers would also like to determine the compound’s specific mechanism of action. Most drug developers try to design molecules with a very specific target. For instance, a molecule might bind to the pocket on an enzyme, thereby stopping the enzyme from doing its job. However, large protein aggregates are unlikely to have specific target sites, a problem that has plagued drug discovery for neurodegenerative diseases. But the fact that Bodner and her colleagues identified a molecule (B2) that could regulate the aggregation process suggests it could be targeted therapeutically, says Finkbeiner.
Compounds such as B2 will help the field even if they don’t directly lead to new drugs, says Robert Pacifici, chief scientific advisor to CHDI, Inc., a nonprofit company that develops therapies for Huntington’s. “They will contribute to the repertoire of tools that will allow us to decipher whether [boosting or preventing aggregation] will be the most fruitful direction for therapy.”