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 Research on alpha-synuclein protein 
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Joined: Fri Dec 31, 2010 3:07 pm
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Location: Minnesota
Post Research on alpha-synuclein protein
A member of my local support group shared this with me. Sounds pretty significant...

New Clue to Parkinson's: Shape of Key Protein Surprises Researchers
ScienceDaily (Aug. 14, 2011) — A new study finds that a protein key to Parkinson's disease has likely been mischaracterized. The protein, alpha-synuclein, appears to have a radically different structure in healthy cells than previously thought, challenging existing disease paradigms and suggesting a new therapeutic approach.
"Our data show that alpha-synuclein was essentially mistakenly characterized as a natively unfolded protein that lacked structure," said Dennis Selkoe, the Vincent and Stella Coates Professor of Neurologic Diseases at Brigham and Women's Hospital and Harvard Medical School and senior author of the paper, published online August 14 in the journal Nature. "We think this discovery has fundamental importance for understanding both how alpha-synuclein normally functions and how it becomes altered in Parkinson's."
When it comes to proteins, function follows form. A protein consists of a chain of chemical building blocks (amino acids), typically folded into an exquisite three-dimensional structure. Each twist and turn in the chain contributes to the protein's unique properties and behavior, so it's critical for scientists to accurately describe the arrangement of folds. But sometimes, they get the entire pattern wrong.
The new study suggests that's just what happened with alpha-synuclein, the protein that forms clumps called Lewy bodies in the brains of patients with Parkinson's and certain related disorders. Scientists have long assumed that alpha-synuclein occurs in healthy cells as a single, randomly-coiled chain that resembles a writhing snake. Selkoe's team has proven, however, that the structure is far more orderly and sophisticated.
"This will open some new therapeutic doors," said first author Tim Bartels, a postdoctoral researcher in Selkoe's lab. "Everybody thought the protein was unfolded, so pharmaceutical companies have focused on preventing unfolded alpha-synuclein from aggregating."
He recommends a new strategy -- keeping the folded form of the protein stable.
How did the true structure of alpha-synuclein in healthy cells evade researchers for so long? Scientists knew that alpha-synuclein was abundant in the brain before they made the connection between the protein and Parkinson's disease in 1997. Experiments in the mid-1990s indicated the protein was stable when exposed to conditions that typically disrupt the structure of most other proteins.
Consider what happens when an egg is boiled: the liquid proteins of the egg white are precipitated by the heat and congeal into a dense white mass. But alpha-synuclein seemed to behave like an egg that remains entirely viscous despite many minutes on the stove. It didn't precipitate and congeal when boiled. This apparent hardiness made alpha-synuclein easy to work with in the lab. Scientists could boil the protein, even douse it with detergents and other rather harsh chemicals, while ostensibly leaving its structure intact.
Bartels and Selkoe wondered whether labs might be overlooking important aspects of the protein's natural biology by handling it so roughly, so they designed experiments to probe alpha-synuclein's behavior using gentler methods. They also bucked a trend by working with protein gathered from human cells rather than from engineered bacteria. The goal was to gain new insight into alpha-synuclein's clustering behavior.
The initial data took them by surprise. Single, isolated chains of alpha-synuclein -- the "monomeric" form of the protein -- were absent from their cellular samples.
"I did my PhD on alpha-synuclein, and -- like the rest of the world -- I assumed that it occurs natively as a monomeric, unfolded protein, so I was shocked," said Bartels.
Using special gels and other methods that are less disruptive to a protein's form, the team conducted additional experiments to explore the structure of alpha-synuclein in healthy blood and brain cells. The native protein was exactly four times the predicted weight of a single alpha-synuclein chain, suggesting that cells package four alpha-synuclein chains together as a "tetrameric" unit. Applying sophisticated equipment and techniques, the team validated the molecular weight of the package, confirmed that it consists solely of alpha-synuclein chains and showed that these four chains have orderly twists.
The researchers observed tetrameric alpha-synuclein to be the dominant form of the protein in healthy human cells, and remarkably resistant to aggregation. The tetramers maintained their original structure for 10 days, the entire length of the experiment, while the team monitored their samples for clustering behavior. In stark contrast, alpha-synuclein monomers began to form clusters after a few days and ended up as large aggregates called amyloid fibers. The Lewy bodies that accumulate in the brains of patients with Parkinson's consist mainly of such amyloid fibers.
"We hypothesize that the folded protein must disassemble into monomers before large pathological aggregates can form," said Selkoe, who is also co-director of the Center for Neurologic Diseases at Brigham and Women's Hospital. "If we can keep alpha-synuclein tetrameric and soluble, we might be able to prevent the neuronal degeneration of Parkinson's disease from progressing -- or perhaps from even developing."
The finding could also prove useful in the quest for new diagnostics. Perhaps ratios of tetrameric protein to monomeric protein in blood cells, serum or spinal fluid will correspond to different propensities or stages of the disease.
Finally, the discovery of the folded tetramers should help labs to uncover the function of alpha-synuclein in healthy cells, which is still much debated. This functional knowledge should, in turn, contribute to researchers' understanding of Parkinson's and other diseases characterized by the formation of Lewy bodies rich in aggregated alpha-synuclein.
This research was funded by the National Institute of Neurological Disorders and Stroke.
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Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Harvard Medical School, via EurekAlert!, a service of AAAS.



Journal Reference:
Tim Bartels, Joanna G. Choi, Dennis J. Selkoe. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature, 2011; DOI: 10.1038/nature10324
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Harvard Medical School (2011, August 14). New clue to Parkinson's: Shape of key protein surprises researchers. ScienceDaily. Retrieved August 15, 2011, from http://www.sciencedaily.com­ /releases/2011/08/110814141449.htm
Note: If no author is given, the source is cited instead.
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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Jeanne, 68 cared for husband Coy, 86. RBD for 30+ years; LDB since 2003, Coy at home, in early stage, until death in 2012


Mon Aug 15, 2011 5:49 pm
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Joined: Wed Dec 30, 2009 1:46 pm
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Location: WA
Post Re: Research on alpha-synuclein protein
I read about this on another forum and found it very exciting news. Hope for future generations, perhaps. Although it has been many years since I took organic chemistry it remains vivid how a molecule's structural shape can drastically affect its function and the way it reacts with other molecules. Neat stuff!

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Pat [68] married to Derek [84] for 38 years; husband dx PDD/LBD 2005, probably began 2002 or earlier; late stage and in a SNF as of January 2011. Hospitalized 11/2/2013 and discharged to home Hospice. Passed away at home on 11/9/2013.


Mon Aug 15, 2011 6:04 pm
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Joined: Fri Aug 11, 2006 1:46 pm
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Location: SF Bay Area (Northern CA)
Post Re: Research on alpha-synuclein protein
Thanks for sharing this.


Mon Aug 15, 2011 11:06 pm
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Location: SF Bay Area (Northern CA)
Post Re: Research on alpha-synuclein protein
Helpfully, there's a 2.5 minute video posted on the research at the link below.

http://www.focushms.com/features/new-cl ... arkinsons/


Mon Aug 15, 2011 11:24 pm
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Joined: Wed Mar 02, 2011 1:04 pm
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Post Re: Research on alpha-synuclein protein
Do I understand this correctly - if they can keep the tetramer from coming apart they could prevent the formation of lewy bodies? Then would that halt the progression of LBD too?
Thanks for posting this Jeanne.....

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First symptoms in 2000 at 35 yrs old. LBD early onset dx 2-17-2011 at age 46.

' "I try not to worry about the future, but rather to "wonder"....and "wonder" is one step away from "awe" '......From a wise friend........


Tue Aug 16, 2011 12:30 am
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Post Re: Research on alpha-synuclein protein
That's the way I see it, Tonya.

_________________
Pat [68] married to Derek [84] for 38 years; husband dx PDD/LBD 2005, probably began 2002 or earlier; late stage and in a SNF as of January 2011. Hospitalized 11/2/2013 and discharged to home Hospice. Passed away at home on 11/9/2013.


Tue Aug 16, 2011 1:06 am
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Post Re: Research on alpha-synuclein protein
Thank you Jeanne and Robin. After I watched the video, I reread the article and could understand a little better. Most of us have children and grandchildren so any positive note is encouraging.
Gerry

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Gerry 67, cared for Frank 71, married 49 yrs; dx 2004, passed away October 26, 2011.


Tue Aug 16, 2011 6:09 am
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Location: SF Bay Area (Northern CA)
Post Re: Research on alpha-synuclein protein
Tonya,
This research, while far away from having any treatment associated with it, has implications for any Lewy body disorder -- Parkinson's Disease, PDD, DLB, and PAF. (I do not think this research has implications for those alpha-synucleinopathies that aren't Lewy body disorders.)
Robin


Tue Aug 16, 2011 10:17 am
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Joined: Wed Mar 02, 2011 1:04 pm
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Post Re: Research on alpha-synuclein protein
It is hopeful that they have this finding - at least I know they are doing active research on PD and LBD and related things.....it's good to know that at least I have something for which there is ongoing research taking place......Before my dx, that was not the case......chronic fatigue syndrome and fibromyalgia were the best dx's I had gotten and a lot of docs don't even believe in those and there is no treatment really or much research on it....so as much as I hate having LBD, I do feel fortunate there are medications I can now take that help and that there is a lot of research going on for dementia...this finding is very hopeful.....perhaps there will be clinical trials before I get past the early stage for something related to this finding? Never know...just grateful for the hope!! Thanks!!

_________________
First symptoms in 2000 at 35 yrs old. LBD early onset dx 2-17-2011 at age 46.

' "I try not to worry about the future, but rather to "wonder"....and "wonder" is one step away from "awe" '......From a wise friend........


Tue Aug 16, 2011 2:24 pm
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Joined: Fri Dec 31, 2010 3:07 pm
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Location: Minnesota
Post Re: Research on alpha-synuclein protein
Thanks for the video, Robin.

I asked Dr. Brad Boeve how significant this discover is. His reply:

These data are from a renowned group, and this may be very important, but like these initial discoveries always go, we don't know how significant this is until the data is replicated and expanded upon. Yet their findings could explain a number of frustrations so far along the therapeutic front, so hope this pans out. Plus, nothing gets published in Nature unless it is a very important discovery.

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Jeanne, 68 cared for husband Coy, 86. RBD for 30+ years; LDB since 2003, Coy at home, in early stage, until death in 2012


Sun Aug 21, 2011 6:12 pm
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Post Re: Research on alpha-synuclein protein
Thanks Jeanne - I printed out what you posted to take to my Neurologist on Sept 8....glad to know Dr. Boeve's opinion as well....will share my doc's after I see her.....

Thanks so much!!!
Tonya

_________________
First symptoms in 2000 at 35 yrs old. LBD early onset dx 2-17-2011 at age 46.

' "I try not to worry about the future, but rather to "wonder"....and "wonder" is one step away from "awe" '......From a wise friend........


Sun Aug 21, 2011 7:22 pm
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Post Re: Research on alpha-synuclein protein
Jeanne,
I wonder what therapies Dr. Boeve is referring to. There are no treatments in humans related to Lewy body formation.
Robin


Mon Aug 22, 2011 3:30 pm
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Joined: Fri Dec 31, 2010 3:07 pm
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Post Re: Research on alpha-synuclein protein
Yeah. I think that is where the frustrations come in. :P

That there are no successful therapies doesn't mean no one is working toward that goal. This new discovery may lead them down more successful paths. At least that is how I read Boeve's response.

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Jeanne, 68 cared for husband Coy, 86. RBD for 30+ years; LDB since 2003, Coy at home, in early stage, until death in 2012


Mon Aug 22, 2011 5:12 pm
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Joined: Mon Mar 21, 2011 11:26 pm
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Location: St Pete Beach, FL
Post Re: Research on alpha-synuclein protein
Someone needs to update the wikipedia page on alpha-synuclein:

http://en.wikipedia.org/wiki/Alpha-synuclein

Particularly the diagram, which still shows the unfolded versions as being the "native" state:


Sat Dec 03, 2011 2:17 pm
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Joined: Tue Mar 29, 2011 3:02 pm
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Location: East TN
Post Re: Research on alpha-synuclein protein
okay….I haven't looked at the research nor the video….
just the summary and your posts….

and Jeanne….what Dr. Boeve said to you….

let me add….

when I last saw him…in early Nov…..

he hinted or danced around….at possible trials possibly in the near future….like something may be in works….
or maybe he is hoping something is in the works…..or I am just dreaming….

But….that was the first time I heard him say something at that level…

rereading this thread, brought this back to mind...

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Craig - Patient - Male - 56 years old - Lewy Bodies diagnosed on March 23, 2011 - cognitive disorder NOS dx 2007 - RBD REM dx 2007 issues for 20+ years - intention tremor 1974 - other issues many years


Sat Dec 03, 2011 2:33 pm
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