New drug lead for Parkinson's disease

Parkinson's disease, which kills off dopamine-producing neurons, is associated with the clumping of misfolded α-synuclein protein into "inclusions" in the brain. Recent evidence supports the notion that neurons form these inclusions to reduce exposure to smaller but more neurotoxic α-synuclein aggregates. Last year, Harvard Medical School biologist Aleksey G. Kazantsev and colleagues identified compounds that reduce toxicity and promote inclusion formation in cellular disease models (Proc. Natl. Acad. Sci. USA 2006, 103, 4246). The researchers discovered that the compounds inhibit the protein sirtuin 2, which interacts with another protein that could conceivably transport small aggregates within cells. Kazantsev and coworkers now have designed and tested 200 additional compounds for their ability to inhibit sirtuin 2 (Science, DOI: 10.1126/science.1143780). The researchers identified several inhibitors with increased potency. These compounds protect dopaminergic neurons from α-synuclein toxicity in cell cultures and in a fruit fly model of Parkinson's, suggesting sirtuin 2 is a promising target for treating the disease.