Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM. 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.
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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.
References:
Ledesma MD, Simons K, Dotti CG. 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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