1 October 2001. 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.), 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.
Reference:Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM. Parkin ubiquitinates the a-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med. 2001 Oct;7(10):1144-50. Abstract