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Toxicity of oligomeric a-synuclein

Posted by Diego_Albani on 09 Apr 2008 at 10:54 GMT

I have read this interesting paper and I would like to discuss some aspect of the authors' findings about the toxicity of oligomeric a-syn.
I have two questions in mind:
a) why the formation of oligomers was detected only in the antiparallel a-syn orientation? A possible explanation is it that in the parallele orientation some steric hindrance took place or this is a peculiar aspect of a-syn oligomers formation?
b) I would expect that mutations of a-syn affect oligomers formation or toxicity in comparison to the wild-type form, but the reported data did not support this point. Is it possible that the time to record toxicity (after 24h) was not sufficient to highlight mutation-specific differences in oligomers toxicity?

Thank you all

RE: Toxicity of oligomeric a-synuclein

touteiro replied to Diego_Albani on 13 Apr 2008 at 20:20 GMT

Thank you for your comments to our work.
To try to answer your questions, what I can say is:
a) You are correct about your interpretation. Steric hindrance may explain this. We were able to detect interactions in the parallel orientation, but these were not "as strong" as the antiparallel interactions. We had already reported similar observations using a different method (FLIM), which makes us believe it may actually be more than just steric hindrance, but the question remains, you are correct.

b) It is possible that the time to record toxicity was not optimal as you suggest. Nevertheless, if mutant a-syn were more toxic than WT, than I would expect to observe toxicity at an even earlier time point. Maybe the 24h time point was already too late to enable us to see those differences...

Best regards to all!