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


  1. The data in this paper provide an impetus for further investigation into synphilin-1 (Sph-1), especially with regards to post-translational modifications. As it has previously been shown that specific phosphorylation events in Sph-1 are necessary for protein aggregation in a cellular setting, experiments to elucidate modifications to this Sph-1A isoform are at an advantageous juncture. One should certainly strive to answer the questions: Which modifications are similar between Sph-1 and Sph-1A and which alterations recapitulate Lewy Body-like formation in neuronal settings? Are these modifications regulated by kinases such as Gsk3b or CKII? What E3 ligases (parkin, Siah, etc) are responsible, if any, for degradation of these modified versions? I would also have to agree with E. Junn and M. Mouradian that it is not clear as to whether or not Sph-1A creates aggregates moreso than its full-length form because of insolubility in Triton-X 100. As the protein was a fusion contruct with the viral protein hemagluttinin (HA), skepticism of their claim becomes paramount since HA has been shown years ago to be inherently insoluble in Triton-X (see ref. below). I would think it is more pertinent to create a non-fusion Sph-1A construct so one could correlate its protein inclusion formation and cytoxicity without an extemporaneous variable. And as that segues into apoptotic effects of Sph-1A, the study done in this paper was over 72 hours and does not indicate long-term effects of their system. Indeed, is not idiopathic Parkinson's disease (PD) a long-term neurodegenerative process? These comments are not meant to nitpick at the limitations of the study so much as they are to generate answerable experiments. I look forward to comments. 


    . Neuronal polarity: essential role of protein-lipid complexes in axonal sorting. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3966-71. PubMed.

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Further Reading


  1. . Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Science. 2001 Jul 13;293(5528):263-9. PubMed.

Primary Papers

  1. . Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med. 2001 Oct;7(10):1144-50. PubMed.