Hitting 'reset' in protein synthesis restores myelination: Suggests new treatment for misfolded protein diseases, such as Charcot-Marie-Tooth, Alzheimer's

Apr. 26, 2013 ? A potential new treatment strategy for patients with Charcot-Marie-Tooth disease is on the horizon, thanks to research by neuroscientists now at the University at Buffalo's Hunter James Kelly Research Institute and their colleagues in Italy and England.

The institute is the research arm of the Hunter's Hope Foundation, established in 1997 by Jim Kelly, Buffalo Bills Hall of Fame quarterback, and his wife, Jill, after their infant son Hunter was diagnosed with Krabbe Leukodystrophy, an inherited fatal disorder of the nervous system. Hunter died in 2005 at the age of eight. The institute conducts research on myelin and its related diseases with the goal of developing new ways of understanding and treating conditions such as Krabbe disease and other leukodystrophies.

Charcot-Marie-Tooth or CMT disease, which affects the peripheral nerves, is among the most common of hereditary neurological disorders; it is a disease of myelin and it results from misfolded proteins in cells that produce myelin.

The new findings sere published online earlier this month in The Journal of Experimental Medicine.

They may have relevance for other diseases that result from misfolded proteins, including Alzheimer's disease, Parkinson's, multiple sclerosis, Type 1 diabetes, cancer and mad cow disease.

The paper shows that missteps in translational homeostasis, the process of regulating new protein production so that cells maintain a precise balance between lipids and proteins, may be how some genetic mutations in CMT cause neuropathy.

CMT neuropathies are common, hereditary and progressive; in severe cases, patients end up in wheelchairs. These diseases significantly affect quality of life but not longevity, taking a major toll on patients, families and society, the researchers note.

"It's possible that our finding could lead to the development of an effective treatment not just for CMT neuropathies but also for other diseases related to misfolded proteins," says Lawrence Wrabetz, MD, director of the institute and professor of neurology and biochemistry in UB's School of Medicine and Biomedical Sciences and senior author on the paper. Maurizio D'Antonio, of the Division of Genetics and Cell Biology of the San Raffaele Scientific Institute in Milan is first author; Wrabetz did most of this research while he was at San Raffaele, prior to coming to UB.

The research finding centers around the synthesis of misfolded proteins in Schwann cells, which make myelin in nerves. Myelin is the crucial fatty material that wraps the axons of neurons and allows them to signal effectively. Many CMT neuropathies are associated with mutations in a gene known as P0, which glues the wraps of myelin together. Wrabetz has previously shown in experiments with transgenic mice that those mutations cause the myelin to break down, which in turn, causes degeneration of peripheral nerves and wasting of muscles.

When cells recognize that the misfolded proteins are being synthesized, cells respond by severely reducing protein production in an effort to correct the problem, Wrabetz explains. The cells commence protein synthesis again when a protein called Gadd34 gets involved.

"After cells have reacted to, and corrected, misfolding of proteins, the job of Gadd34 is to turn protein synthesis back on," says Wrabetz. "What we have shown is that once Gadd34 is turned back on, it activates synthesis of proteins at a level that's too high -- that's what causes more problems in myelination.

"We have provided proof of principle that Gadd34 causes a problem with translational homeostasis and that's what causes some neuropathies," says Wrabetz. "We've shown that if we just reduce Gadd34, we actually get better myelination. So, leaving protein synthesis turned partially off is better than turning it back on, completely."

In both cultures and a transgenic mouse model of CMT neuropathies, the researchers improved myelin by reducing Gadd34 with salubrinal, a small molecule research drug. While salubrinal is not appropriate for human use, Wrabetz and colleagues at UB and elsewhere are working to develop derivatives that are appropriate.

"If we can demonstrate that a new version of this molecule is safe and effective, then it could be part of a new therapeutic strategy for CMT and possibly other misfolded protein diseases as well," says Wrabetz.

And while CMT is the focus of this particular research, the work is helping scientists at the Hunter James Kelly Research Institute enrich their understanding of myelin disorders in general.

"What we learn in one disease, such as CMT, may inform how we think about toxins for others, such as Krabbe's," Wrabetz says. "We'd like to build a foundation and answer basic questions about where and when toxicity in diseases begin."

The misfolded protein diseases are an interesting and challenging group of diseases to study, he continues. "CMT, for example, is caused by mutations in more than 40 different genes," he says. "When there are so many different genes involved and so many different mechanisms, you have to find a unifying mechanism: this problem of Gadd34 turning protein synthesis on at too high a level could be one unifying mechanism. The hope is that this proof of principle applies to more than just CMT and may lead to improved treatments for Alzheimer's, Parkinson's, Type 1 diabetes and the other diseases caused by misfolded proteins."

Co-authors with D'Antonio and Wrabetz are M. Laura Feltri, MD, professor of neurology and biochemistry at UB and a researcher with UB's Hunter James Kelly Research Institute at the NYS Center of Excellence in Bioinformatics and Life Sciences; Nicolo Musner, Cristina Scapin Daniela Ungaro and Ubaldo Del Carro from the San Raffaele Scientific Institute and David Ron of Cambridge and the National Institute for Health Research Cambridge Biomedical Research Centre.

Funding was provided by the National Institutes of Health, the European Community and an award to D'Antonio from the Italian Ministry of Health.

Share this story on Facebook, Twitter, and Google:

Other social bookmarking and sharing tools:

---

Story Source:

The above story is reprinted from materials provided by University at Buffalo. The original article was written by Ellen Goldbaum.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

---

Journal Reference:

1. M. D'Antonio, N. Musner, C. Scapin, D. Ungaro, U. Del Carro, D. Ron, M. L. Feltri, L. Wrabetz. Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice. Journal of Experimental Medicine, 2013; 210 (4): 821 DOI: 10.1084/jem.20122005

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.

Source: http://feeds.sciencedaily.com/~r/sciencedaily/~3/_o1zELs2WuM/130426135037.htm

nevis 2012 sports illustrated swimsuit same day flower delivery valentines day cards hallmark grammy winners obama budget

Of one mind about chemical weapons and protecting the innocent

Probable evidence of chemical-gas use in Syria may soon force world leaders to intervene. Their decision should be based on a principle enshrined in a global ban of such weapons ? a respect for the innocence of civilians in not being harmed by this indiscriminate tool of war.

By the Monitor's Editorial Board / April 26, 2013

In a March 21 speech in Jerusalem, President Obama gestured strongly as he said: "I?ve made it clear to Bashar al-Assad and all who follow his orders: We will not tolerate the use of chemical weapons against the Syrian people, or the transfer of those weapons to terrorists. The world is watching; we will hold you accountable."

AP Photo

Enlarge

From afar, the probable use of chemical weapons by the Syrian regime could seem like just more Middle East mayhem. Yet it is not. Which is why President Obama and other world leaders are contemplating stiff action in Syria based on evidence of at least one sarin-gas attack.

Skip to next paragraph

' + google_ads[0].line2 + '
' + google_ads[0].line3 + '

'; } else if (google_ads.length > 1) { ad_unit += ''; } } document.getElementById("ad_unit").innerHTML += ad_unit; google_adnum += google_ads.length; return; } var google_adnum = 0; google_ad_client = "pub-6743622525202572"; google_ad_output = 'js'; google_max_num_ads = '1'; google_feedback = "on"; google_ad_type = "text"; google_adtest = "on"; google_image_size = '230x105'; google_skip = '0'; // -->

Subscribe Today to the Monitor

Click Here for your FREE 30 DAYS of
The Christian Science Monitor
Weekly Digital Edition

More than other tools of war, chemical weapons are indiscriminate in what they strike. Poisonous gases can float anywhere. They can wipe out entire populations of civilians, either by design or a change of wind. Even the weapon?s users might be hit.

For these reasons, nations have gradually agreed since 1899, or at the dawn of modern warfare, to tougher sanctions against these tools of destruction. In 1997, the Chemical Weapons Convention came into force with the support of 188 states.

This steady toughening of rules is not simply because of the immense fear such weapons evoke by their effects. It is because enough people have made a conscious choice to protect the innocent ? or the very idea of innocence as the preferred condition of every human being.

As humanitarian scholar Hugo Slim wrote in a 2008 book about civilian protection, ?The main idea behind limited war and its civilian ethic is, of course, that of limited killing. This is because every human being?s life is precious to themselves, to those who love them and, if one is religious, to God as well.?

As the United States and others now debate their next steps in Syria, this century-long progress toward a near-universal acceptance of protecting the innocent from an indiscriminate weapon should be a guiding principle.

Obama and others, of course, have strategic and tactical concerns. Would outside intervention cause even more use of chemical weapons? Would a foreign invasion lead to high civilian casualties? Can an over-indebted and war-weary Europe or US afford to act?

Even deciding who is a civilian is often difficult. The Geneva Conventions define civilians for what they are not ? as not a warrior or someone directly helping a war. But what about a teacher of militant Islam? Or a teenage army conscript? What of the Syrian civilians who give bread to rebels?

And then there is the possibility that Syrian President Bashar al-Assad may have simply allowed a small chemical attack as a bargaining chip in possibly negotiating an end to this civil war.

Given the history of the Iraq invasion, Washington might not want to rely on its own evidence of gas having been used in Syria to lead a campaign for the United Nations to act. And the US has a mixed record of protecting civilians in war, although it is a record far better than that of its foes in recent wars.

As careful as the Obama administration has been in using predator drones to strike terrorists, for example, this aerial weapon is generally less effective than the use of soldiers on the ground in avoiding ?collateral damage? to civilians.

Obama has described the use of chemical weapons by the Assad regime as a ?game changer.? The killing of civilians with Syrian fighter jets and other conventional means ? more than 70,000 ? has not yet pushed the US or others to militarily intervene. But letting the regime break international norms on chemical weapons would set a big precedent and erode a global consensus on a major humanitarian rule of war.

Respect for innocent life lies at the heart of most rules of war. Not every intended war-time attack on civilians can be prevented. But some attacks matter far more than most. Knowing the principle at stake in chemical warfare should help world leaders make the right decision on Syria.

Source: http://rss.csmonitor.com/~r/feeds/csm/~3/h0mC8TH-ROI/Of-one-mind-about-chemical-weapons-and-protecting-the-innocent

d rose iman shumpert mayweather vs cotto shumpert hopkins hopkins dear john

MTA And Transit Wireless Expands Coverage To 30 NYC Underground Subway Stations

At last. Starting today, the MTA is switching on wireless and cellular connectivity in 30 underground subway stations around Manhattan, and the fledgling network will expand to all 277 of the MTA?s subway stations by 2016.

Source: http://feedproxy.google.com/~r/Techcrunch/~3/07jrpWsO-og/

eagles nfl schedule 2012 Fox News Suicide Google Ryder Cup Standings Dexter Season 7 Ryder Cup 2012

S.C. governor takes out ad space in battle over trespassing

Mark Sanford ad (screenshot)

Mark Sanford apparently decided the best way to battle charges of trespassing on ex-wife Jenny Sanford's property was to purchase a full-page newspaper ad.

?It?s been a rough week," the former South Carolina governor writes in the ad in Charleston's Post & Courier, which aims to clear the air as he heads into a competitive May 7 House special election race.

Sanford, who famously disappeared in 2009 to "hike the Appalachian trail" when he was vacationing with his mistress, published the ad over the weekend to respond to Jenny Sanford's complaints that he trespassed on her property during the Super Bowl.

Reiterating statements he released last week, Sanford said he had been unable to reach his ex-wife, who was apparently out of town at the time, to ask permission to come into the house to watch the Super Bowl with their 14-year-old son.

He suggested that the release of the trespassing complaints, which were sealed in court documents, had been politically motivated, noting "the unusual timing of supposedly sealed documents coming to light two weeks before an election." Then he details his and his wife's desire to protect their family.

Sanford even gave out his cellphone number.

The ad follows a week filled with media coverage of the trespassing complaints and political back-and-forth over the accusations in South Carolina. In a telling decision, the National Republican Congressional Committee announced shortly after the charges came to light that it would no longer invest in his race against Democratic candidate Elizabeth Colbert Busch.

Sanford's campaign has struggled to stay afloat.

Source: http://news.yahoo.com/blogs/ticket/mark-sanford-takes-full-page-ad-offers-cell-205227328--election.html

purim acc tournament big ten tournament big east tournament 2012 solar storm solar flares spanx

Maine gas prices down nearly a nickel per gallon

AUGUSTA, Maine (AP) -- The average retail cost of a gallon of gas in Maine is down by another nickel.

Price-monitoring website MaineGasPrices.com reports Monday that gas has dropped to an average of $3.53 per gallon.

That's just three cents higher than the national average, almost 22 cents lower than a month ago, and nearly 41 cents lower than at the same time last year.

The dropping prices are unusual, as prices usually rise in the spring.

The Maine prices are based on a survey of more than 1,200 gas stations across the state.

Source: http://news.yahoo.com/maine-gas-prices-down-nearly-145850855.html

iTunes Alfred Morris weight watchers fandango google play Christmas Story after christmas sales

Kerry says doubling U.S. non-lethal aid to Syrian opposition

By David Brunnstrom

ISTANBUL (Reuters) - U.S. Secretary of State John Kerry said on Sunday that the United States would double its non-lethal aid to opposition forces in Syria to $250 million and that foreign backers had agreed to channel all future assistance through the rebels' Supreme Military Council.

Kerry stopped short of a U.S. pledge to supply weapons to insurgents fighting to overthrow Syrian President Bashar al-Assad that the rebels have sought.

But he said that the rebels' foreign backers were committed to continuing support to them and "there would have to be further announcements about the kind of support that that might be in the days ahead" if Syrian government forces failed to pursue a peaceful solution to the crisis.

Speaking after a meeting of the Syrian opposition and its 11 main foreign supporters in Istanbul, Kerry said the United States would provide an additional $123 million in non-lethal assistance to the rebels, bringing the total of this kind of U.S. help to $250 million.

Kerry urged other foreign backers to make similar pledges of assistance with the goal of reaching $1 billion in total international support.

A U.S. official said on Friday that new non-lethal U.S. aid could include for the first time battlefield support equipment such as body armor and night-vision goggles. U.S. officials have said in the past that the equipment could include armored vehicles and advanced communications equipment, but Kerry gave no specifics.

He said the United States would work with the Syrian opposition to determine how the money would be spent and added that Washington would also provide nearly $25 million in additional food aid.

Kerry said the foreign supporters had "all committed that the aid and assistance from every country will go through the (rebel) Supreme Military Command."

"Today, it's safe to say that we are really at a critical moment," Kerry said. "The stakes in Syria couldn't be more clear: Chemical weapons, the slaughter of people by ballistic missiles and other weapons of huge destruction. The potential of a whole country, a beautiful country with great people, being torn apart and perhaps breaking up into enclaves (with the) potential of sectarian violence which this region knows there is too much of.

"What we are trying to do is to avoid all of that. And we committed to - we recommitted - because we think there are some people who don't believe that we believe it, or are in fact are committed to it," he said.

Kerry referred to a statement issued after the meeting by Syria's main opposition National Coalition in which it pledged not to use chemical weapons, rejected "all forms of terrorism" and vowed that weapons it attains would not fall into the wrong hands.

In its declaration outlining its vision of a post-Assad Syria and issued following the "Friends of Syria" meeting with Western and Arab backers, the coalition also said it would not allow acts of revenge against any group in Syria.

The latest U.S. expansion of non-lethal aid follows Kerry's announcement in Rome in late February that Washington would shift policy to provide medical supplies and food directly to opposition fighters, an option it had previously rejected.

Despite pressure from some members of Congress and recommendations even from among his own advisers, U.S. President Barack Obama has refused to supply arms to the rebels, reflecting concern that such weapons would fall into the hands of Islamist militants in the ranks of the fractious insurgency.

However, even the limited new steps under consideration suggest that the White House, amid difficult internal debate, is continuing to move slowly toward a more direct role in bolstering the Syrian opposition.

Saudi Arabia and Qatar are among Arab states believed to be arming rebel factions.

(Editing by Robin Pomeroy, Eric Walsh and Paul Simao)

Source: http://news.yahoo.com/kerry-says-doubling-u-non-lethal-aid-syrian-000555607.html

apple earnings report john l smith apple earnings the glass castle jennifer hudson trial north korea threat

Storytelling Techniques For Effective Business Communications ...

The grab-bag post makes a second appearance in 2013.

Crafted for easy consumption, the grab-bag posts are for recreational amusement only.

Economist Calls Increase in PR Professionals a ?Pernicious Trend?

Thankfully, my dictionary sits a click away.

Well, that doesn?t sound all that positive.

The Economist story goes on to leverage its crack data scientists who, after crunching and correlating the numbers, generated this ditty:

• 2008 Ratio of PR professionals to journalists: 4:1

Now there?s an alert-the-media revelation that explains the plight of journalism.

But Enough About Me; Let?s Talk About Me

With the Tiger Woods marketing machine again running on full throttle, his agent Mark Steinberg conducted an interview with Businessweek that made one point clear:

?I try to not let anything be about me. It?s about my clients. I kind of stay behind the scenes.?

Dude, talking to Diane Brady for the ?Hard Choices? back page of Businessweek is not behind the scenes.

Then again, this line in the same story says it all:

?I don?t know if I?m a good agent or a great agency or a legendary agency.?

There?s a Place for Sweating in Public Speaking

Like before.

This guidance for public speaking comes from George Plimpton:

The more you sweat in advance, the less you?ll have to sweat once you appear on stage.

Plimpton goes on to emphasize the importance of old-fashioned research:

Check the library for facts, quotes, books, and timely magazine and newspaper articles on your subject. Get in touch with experts. Write to them, make phone calls, get interviews to help round out your material.

While going to the library sounds quaint ? keep in mind this was written pre-Internet ? the point to learn far more than you?ll ever use in your talk is good advice.

Source: http://www.ishmaelscorner.com/2013/04/18/pernicious-pr-people-ego-in-branding-public-speaking-no-sweat/

new jersey nets nba playoff schedule rondo morris claiborne mothers day gifts clippers lisa lampanelli

How the Dow Jones industrial average did Thursday

Disappointing earnings from a range of companies pushed the stock market lower on Thursday, giving major indexes their third loss this week.

The stock prices of Morgan Stanley, UnitedHealth Group and others sank after they turned in weaker quarterly results. Prices of commodities held steady following a wild couple of days.

The Dow Jones industrial average fell 81.45, or 0.6 percent, to close at 14,537.14.

The Standard & Poor's 500 index lost 10.40 points, or 0.7 percent, to 1,541.61.

The Nasdaq composite fell 38.31 points, or 1.2 percent, to 3,166.36.

For the week:

The Dow is down 327.92 points, or 2.2 percent.

The S&P 500 is down 47.24 points, or 2.9 percent.

The Nasdaq is down 128.59 points, or 3.9 percent.

For the year:

The Dow is up 1,433.00 points, or 10.9 percent.

The S&P 500 is up 115.42 points, or 8.1 percent.

The Nasdaq is up 146.85 points, or 4.9 percent.

Source: http://news.yahoo.com/dow-jones-industrial-average-did-215644889.html

St Patrick lisa vanderpump Dancing With the Stars 2013 NIT Bracket March Madness 2013 bracket March Madness 2013 selection sunday

PFT: Harrison reportedly nearing deal with Bengals

Getty Images

As more and more teams become aware of the risks associated with the potent painkiller Toradol, more and more team doctors are shying away from giving it to players.

As part of a thorough look at the use of medication by NFL teams to allow players to suit up on Sundays, Sally Jenkins and Rick Maese of the Washington Post explain that some teams have decided to use it less frequently, or not at all.

Rams physician Matt Matava decided after taking a closer look at Toradol?s side effects and balancing the risks with the benefits to ?essentially eliminate[]? it from the team?s locker room.

?We had two players come up to me at the very first game and said, ?I?m here for my Toradol shot,?? Dr. Matava said. ?I said, ?We?re not using it anymore.?? ?Okay, can I have something else??? I never heard one more word about it the rest of the season.?

Other teams now avoid it ?whenever possible,? including the Packers, Falcons, and Redskins.

The drug first gained wide notice in January 2012, via a segment from HBO?s Real Sports with Bryant Gumbel.? Players like Brian Urlacher told Andrea Kremer that he hadn?t been told about potential kidney damage or gastrointestinal bleeding.? Once aware of the potential risks, Urlacher said he?d still take it.

Players balked at efforts to restrict the use of Toradol in 2012, and then a grievance was filed after at least one team required players receiving it to sign a waiver of legal claims that among other things referred players to Wikipedia for more information about the drug.

For the men who play the game, it?s a delicate balance.? They want to be able to perform without pain, but they also need to be fully aware of the risks.

The problem is that, because the drug wasn?t designed to help football players feel invincible on game days, the full range of risks isn?t completely known.? At some point, the doctors entrusted with player care must be willing to say that it?s better to not be able to play than to artificially mask pain with a drug that can do more harm that good over the long haul.

Source: http://profootballtalk.nbcsports.com/2013/04/14/bengals-getting-closer-to-deal-with-james-harrison/related/

julio jones j crew san francisco 49ers san francisco 49ers stan musial Mega 49ers