01/22/2019

Parkinson’s disease stopped in animal model

By Live Dr - Mon Mar 05, 12:09 am

Millions of people suffer from Parkinson’s disease, a disorder of the nervous system that affects movement and worsens over time. As the world’s population ages, it’s estimated that the number of people with the disease will rise sharply. Yet despite several effective therapies that treat Parkinson’s symptoms, nothing slows its progression.

Artist’s rendering of neurons. (Credit: iStockphoto)

While it’s not known what exactly causes the disease, evidence points to one particular culprit: a protein called α-synuclein. The protein, which has been found to be common to all patients with Parkinson’s, is thought to be a pathway to the disease when it binds together in “clumps,” or aggregates, and becomes toxic, killing the brain’s neurons.

Now, scientists at UCLA have found a way to prevent these clumps from forming, prevent their toxicity and even break up existing aggregates.

UCLA professor of neurology Jeff Bronstein and UCLA associate professor of neurology Gal Bitan, along with their colleagues, report the development of a novel compound known as a “molecular tweezer,” which in a living animal model blocked α-synuclein aggregates from forming, stopped the aggregates’ toxicity and, further, reversed aggregates in the brain that had already formed. And the tweezers accomplished this without interfering with normal brain function.

The research appears in the current online edition of the journal Neurotherapeutics.

There are currently more than 30 diseases with no cure that are caused by protein aggregation and the resulting toxicity to the brain or other organs, including Parkinson’s, Alzheimer’s and Type 2 diabetes. It is therefore critical, Bronstein said, to find a way to stop this aggregation process. Over the last two decades, researchers and pharmaceutical companies have attempted to develop drugs that would prevent abnormal protein aggregation, but so far, they have had little or no success.

While these aggregates are a natural target for a drug, finding a therapy that targets only the aggregates is a complicated process, Bronstein said. In Parkinson’s, for example, the protein implicated in the disorder, α-synuclein, is naturally ubiquitous throughout the brain.

“Its normal function is not well understood, but it may play a role in aiding communication between neurons,” Bronstein said. “The trick, then, is to prevent the α-synuclein protein aggregates and their toxicity without destroying α-synuclein’s normal function, along with, of course, other healthy areas of the brain.

Molecular tweezer

Bronstein collaborated with Bitan, who had been working with a particular molecular tweezer he had developed called CLR01. Molecular tweezers are complex molecular compounds that are capable of binding to other proteins. Shaped like the letter “C,” these compounds wrap around chains of lysine, a basic amino acid that is a constituent of most proteins.

Working first in cell cultures, the researchers found that CLR01 was able to prevent α-synuclein from forming aggregates, prevent toxicity and even break up existing aggregates.

“The most surprising aspect of the work,” Bronstein said, “is that despite the ability of the compound to bind to many proteins, it did not show toxicity or side effects to normal, functioning brain cells.”

“We call this unique mechanism ‘process-specific,’ rather than the common protein-specific inhibition,” Bitan added, meaning the compound only attacked the targeted aggregates and nothing else.

The researchers next tried their tweezers in a living animal, the zebrafish, a tropical freshwater fish commonly found in aquariums. The zebrafish is a popular animal for research because it is easily manipulated genetically, develops rapidly and is transparent, making the measurement of biological processes easier.

Using a transgenic zebrafish model for Parkinson’s disease, the researchers added CLR01 and used fluorescent proteins to track the tweezer’s effect on the aggregations. They found that, just as in cell cultures, CLR01 prevented α-synuclein aggregation and neuronal death, thus stopping the progression of the disorder in the living animal model.

Being able to prevent α-synuclein from aggregating, prevent toxicity and break up existing aggregates is a very encouraging result, but still, at the end of the day, “we’ve only stopped Parkinson’s in zebrafish,” Bronstein said.

“Nonetheless,” he said, “all of these benefits of CLR01 were found without any evidence of toxicity. And taken together, CLR01 holds great promise as a new drug that can slow or stop the progression of Parkinson’s and related disorders. This takes us one step closer to a cure.”

The researchers are already studying CLR01 in a mouse model of Parkinson’s and say they hope this will lead to human clinical trials.

Other authors of the study included Shubhangi Prabhudesai, Sharmistha Sinha, Aida Attar, Aswani Kotagiri, Arthur G. Fitzmaurice, Ravi Lakshmanan, Magdalena I. Ivanova, Joseph A. Loo and Mark Stahl, all of UCLA, and Frank-Gerrit Klärner and Thomas Schrader of the University of Duisburg-Essen in Germany.

Funding was provided by multiple sources, including the Levine Foundation, the American Health Assistance Foundation, the UCLA Jim Easton Consortium for Alzheimer’s Drug Discovery and Biomarker Development, the Team Parkinson/Parkinson Alliance, and the National Institutes of Health.

Link:sciencedaily.com

171 Comments

Comments 151 - 171 of 171First« PrevNext »Last
  1. Please let me know if you’re looking for a writer for your blog.

    You have some really good articles and I think I would
    be a good asset. If you ever want to take some of the load off, I’d love to
    write some content for your blog in exchange for a link back to
    mine. Please shoot me an e-mail if interested. Cheers!

    Napoli Fotballdrakt

  2. time to look over it all at the moment but I have saved it and also added in your RSS feeds, so when

  3. Thank you ever so for you blog article.Really thank you! Cool.

  4. This is really interesting, You are a very skilled blogger. I ave joined your feed and look forward to seeking more of your excellent post. Also, I have shared your web site in my social networks!

  5. just beneath, are quite a few totally not associated sites to ours, having said that, they’re surely really worth going over

  6. Your mode of describing all in this piece of writing is genuinely pleasant,
    every one be able to simply know it, Thanks a lot.

    fotbollströjor barn

  7. It’s an amazing article in favor of all the online viewers;
    they will get benefit from it I am sure.

    billige fotballdrakter

  8. This info is worth everyone’s attention. When can I find out more?

    maglie del calcio

  9. I think that is one of the most important info for me. And i’m glad reading your article.

    But want to statement on some basic things, The web site style is
    perfect, the articles is really excellent : D. Good task, cheers

    fotbollströjor

  10. Wonderful article! That is the kind of info that are supposed to be shared around
    the web. Shame on Google for not positioning this submit
    upper! Come on over and discuss with my site . Thanks =)

    maglie calcio bambino

  11. Hi there, i read your blog from time to time and i own a similar one and i
    was just wondering if you get a lot of spam responses?
    If so how do you stop it, any plugin or anything you can recommend?
    I get so much lately it’s driving me crazy so any support is very much appreciated.

    fodboldtrøjer online

  12. After looking at a handful of the blog posts on your blog, I
    truly appreciate your technique of writing a blog.
    I bookmarked it to my bookmark site list and will be checking back soon.
    Please check out my website as well and tell me your opinion.

    fotbollskläder

  13. I am truly thankful to the owner of this website who has shared this impressive post at at this time.

    fotballdrakter

  14. I am no longer certain where you’re getting your info,
    however good topic. I must spend some time finding out much more or working out more.
    Thanks for great info I was on the lookout for this information for my mission.

    maglie calcio bambino

  15. Hey There. I found your blog using msn. This is a very well written article.
    I’ll be sure to bookmark it and return to read more of your
    useful information. Thanks for the post. I’ll certainly comeback.

    maglie del calcio

  16. This design is incredible! You certainly know how to keep a reader entertained.
    Between your wit and your videos, I was almost moved to start my own blog (well, almost…HaHa!) Wonderful job.
    I really loved what you had to say, and more than that, how you presented it.
    Too cool!

    fotballdrakter

  17. This is a topic that’s near to my heart… Best wishes!
    Where are your contact details though?

    maglie calcio bambino

  18. Magnificent items from you, man. I have take note your stuff prior to and you are just too fantastic.
    I really like what you’ve received here, really like what you are stating and the way in which by which
    you are saying it. You’re making it entertaining and you continue to care
    for to stay it sensible. I can not wait to learn far
    more from you. That is really a great web site.

    fodboldtrøjer online

  19. Very descriptive article, I loved that bit. Will there be a part 2?

    Manchester United fodboldtrøje med tryk

  20. Revitalized snare work:
    http://katrina.go.telrock.net

  21. Have you tried twitterfeed on your blog, i think it would be cool.*”\””

    https://www.playbuzz.com/item/8296e798-822e-4e1e-b03a-622155e18c50

Comments 151 - 171 of 171First« PrevNext »Last

Leave a Reply