Is there a biochemical explanation for Parkinson's risk in Sergey Brin's self-reported mutation in LRRK2 protein?
Maxine Clarke
Friday, 26 September 2008 11:37 UTC
From Discovering biology in a digital world blog
‘Lots of bloggers in the DNA network have been busy these past few days writing about Google’s co-founder Sergey Brin, his blog, his wife’s company (23andme), and his mutation in the LRRK2 gene.
I was a little surprised to see that while other bloggers have been arguing about whether or not the mutation really increases the risk to the degree (20-80%) mentioned by Brin, no one has really looked into the structure and biochemistry of the LRRK2 protein to see if there’s a biochemical explanation for Parkinson’s risk. I guess that task is up to me.’
Read on here.
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Replies
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Anonymous
Hi, Maxine,
“one particular mutation of the LRRK2 gene — known as G2019S — that, while rare even among people with the disease, accounts, in some ethnic groups, for a substantial proportion of familial Parkinson’s.”
By mutation of selected residues to smaller amino acids like Gly, as Ala/Ser to Gly mutations, the flexibility at or near the active site of a protein should be increased.
Leucine rich repeat structure was commented in this week Science article, “Antigen Recognition by Variable Lymphocyte Receptors”. The LRR modules of the solenoid structures interact with a protein partner in plant-pathogen interactions, or with H-antigen trisaccharide in human antigen recognition and specificity. So one possible answer is that the flexibility of the solenoid structure has changed. But which is the partner in these protein-protein complexes?
It would require a co-precipitation technique, using recombinant LRRK2. -
sorry for the “anonymous”, I blogged with my log in data,
Palmiro Poltronieri -
Thanks, Palmiro. Sally Church writes at Friend Feed:
I thought the author [i.e. author of blog post I’ve quoted from above] was stretching the conclusion a bit in saying, “you have a pretty good chance of getting Parkinson’s, unless there’s some other amino acid change that compensates for the more active kinase.” There isn’t enough evidence to substantiate that claim yet. -
I’ve read a couple of cynical blog posts on this topic that highlight the great cross marketing undertaken by Brin, but likewise I’ve generally found that bloggers are pretty circumspect about what the results of such genetic tests actually mean.
I’ve not come across any posts on the mechanism by which the LRRK2 protein might cause Parkinson’s though. On the other hand, I don’t read many genetics/cell biology blogs – this kind of stuff gives me a headache!
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I think that is why the blogger I quote in my forum entry decided to have a go at doing so, Helen, but I think it is pure speculation at this stage of knowledge. Sally Church seems to think so over at FriendFeed.
I thought Sergey Brin’s post in itself was a good post about the personal struggles in dealing with such information, but as usual, reactions elsewhere, mainly in the media, were ludicrously exaggerated and uncomprehending. (As has been discussed at FF also.)
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I found the post by Sandra Porter very informative. Well, my previous reply was written on the spur of the moment, but it was not completely wrong. Now, with all the information, and after checking the OMIM reference, I now understand that something goes wrong within the LRRK2 dimer, causing protein aggregate formation that trigger dopaminoceptive neuron death. Being located within the activation loop, the glycine may be required for the contribution to a rigid alpha helic, and the gain in flexibility may influence the active site, keeping the tyrosine too far from the aspartate (considering the dimer, it should be investigated whether both the TYR in LRRK2 proteins in the dimer need to be phosphorylated…)
One task for the pharma industry is to find peptides or aptamers to preserve the wild type protein or restore the integrity of the dimer by forcing the active loop in a native conformation.Palmiro Poltronieri
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Hey those of you who feel biochemistry-challenged!
Not to worry! I have an educational activity that covers a different form of Parkinson’s disease and I’d like to see if doing this activity helps you out.
You can find the activity here:
Want to learn about genetics? Play with molecular modeling? I need volunteers
Thanks!
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