One of the hallmarks of sporadic Parkinson's disease (PD) are Lewy bodies (LB), neuronal cytoplasmic inclusions that contain ubiquitinated proteins. Recently researchers have focused on two key LB components, the 16 kDa α-synuclein, and the ubiquitin-ligase parkin, because mutations in both of these proteins are responsible for familial forms of PD. Though a 22 kDa posttranslationally modified form of α-synuclein is ubiquitinated by parkin (Shimura et al., 2001), attempts to connect the ligase to unmodified α-synuclein have so far proven unsuccessful.
Work from the lab of Ted and Valina Dawson at Johns Hopkins University, Baltimore, Maryland, published today in Nature Medicine, now reveals that parkin interacts with the α-synuclein-associated protein synphilin-1, another LB component. The authors found that parkin and synphilin-1 coimmunoprecipitate from cell culture extracts and from rat brain homogenates. The interaction was localized to the second ring finger domain of parkin (R2) and the ankyrin domain of synphilin. Mutations in the R2 domain, which are associated with familial forms of PD, were found not only to increase the strength of the interaction, but also to inhibit or even abolish ubiquitination of synphilin. In addition, coexpression of all three proteins resulted in the formation of ubiquitinated inclusion bodies in vitro, yet when mutated forms of parkin were substituted for wild type the number of ubiquitinated inclusions dropped nearly 20-fold.
"This is a wonderful piece of work that closes the loop between parkin and α-synuclein," said Michael Schlossmacher, a neurologist at Brigham and Women's Hospital in Boston. "Perhaps more importantly, the authors have generated inclusion bodies in vitro that are morphologically very similar to Lewy bodies. These may serve as useful models for further study."—Tom Fagan