Researchers at the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND) identified a potential new drug target for the treatment of Parkinson’s disease and possibly for other degenerative neurological disorders.
In an upcoming issue of Science, the investigators report that, in cellular and animal models, blocking the action of the enzyme, SIRT2, can protect the neurons damaged in Parkinson’s disease from the toxic effects of alpha-synuclein, a protein that accumulates in the brains of patients. The study also suggests that inhibiting this pathway could help in the treatment of other conditions in which abnormal proteins accumulate in the brain.
MGH-MIND investigators discovered that in Parkinson’s the alpha-synuclein molecule folds abnormally and forms aggregates called inclusion bodies. Such inclusions of other abnormal proteins are seen in several disorders, but whether inclusions are toxic or protective to neurons has been controversial, the team says.
In a paper published last year in the Proceedings of the National Academy of Sciences, a research team led by Aleksey Kazantsev, Ph.D., director of MGH-MIND drug discovery laboratory, analyzed ways to reduce the size of inclusions containing misfolded versions of alpha-synuclein or of the Huntington’s disease-associated protein huntingtin. They found that a compound called B2, which promotes the formation of larger inclusions, appeared to reduce toxicity in cellular disease models, possibly by reducing the overall number of inclusions.
In the current study, Dr. Kazantsev and his team began by seeking the mechanism underlying the observed effects of B2. Assays of the compound’s activity against a panel of key enzymes identified only one significant association—a weak but selective inhibition of SIRT2, which is known to regulate the cell cycle and may have a role in aging. An experiment using RNAi to suppress SIRT2 and a related enzyme in human cell lines expressing alpha-synuclein confirmed that only the inhibition of SIRT2 reduced alpha-synuclein toxicity.
The scientists then developed and identified more powerful inhibitors of SIRT2, based on the structure of B2. They note that one of these, AGK2, had 10 times the potency of B2 and protected dopamine-producing neurons from alpha-synuclein toxicity in cultured rat neurons and in an insect model.
Several additional compounds that act on the SIRT2 pathway have been identified, according to MGH-MIND, some which may be even better than AGK2 as candidates for drug development.
The researchers theorize that inhibiting SIRT2 might promote microtubule-dependent transportation of alpha-synuclein into large aggregates or could strengthen microtubules that have been destabilized by misfolded alpha-synuclein.
“For Parkinson’s disease, we can now pursue a straightforward drug development process by identifying potent and selective candidates from this class of compounds,” notes Dr. Kazantsev.
"Since the same sort of aggregation of misfolded proteins has been reported in Huntington's and Alzheimer's diseases as well as Lewy body dementia, which also involves alpha-synuclein deposits,” he adds, “we plan to test this approach in those conditions as well."