Trust your gut: E. coli may hold one of the keys to treating Parkinson's

22-Jan-2015 University of Michigan

ANN ARBOR--E. coli usually brings to mind food poisoning and beach closures, but researchers recently discovered a protein in E. coli that inhibits the accumulation of potentially toxic amyloids--a hallmark of diseases such as Parkinson's.

Amyloids are formed by proteins that misfold and group together, and when amyloids assemble at the wrong place or time, they can damage brain tissue and cause cell death, according to Margery Evans, lead author of the University of Michigan study, and Matthew Chapman, principal investigator and associate professor in U-M Molecular, Cellular, and Developmental Biology. 

The findings could point to a new therapeutic approach to Parkinson's disease and a method for targeting amyloids associated with such neurodegenerative diseases.

A key biological problem related to patients with Parkinson's is that certain proteins accumulate to form harmful amyloid fibers in brain tissues, which is toxic to cells and causes cell death. 

While these amyloids are a hallmark of Parkinson's and other diseases such as Alzheimer's, not all amyloids are bad. Some cells, those in E. coli included, assemble helpful amyloids used for cell function. 

E. coli make amyloid curli on the cell surface, where it's protective, rather than toxic. The curli anchor the bacteria to kitchen counters and intestinal walls, where they can cause infections and make us sick. These helpful amyloids that E. coli produce do not form on the inside of the cell where they would be toxic.

"It means that something in E. coli very specifically inhibits the assembly of the amyloid inside the cell. Therefore, amyloid formation only occurs outside the cell where it does not cause toxicity," said Evans, a doctoral student in molecular, cellular, and developmental biology. 

Evans and the U-M team went on a biochemical hunt to understand how E. coli prevented amyloids from forming inside cells and uncovered a protein called CsgC that is a very specific, effective inhibitor of E. coli amyloid formation.

U-M researchers have been collaborating with scientists from Umeå University in Sweden and Imperial College in London, and in the current study found that the CsgC protein also inhibits amyloid formation of the kind associated with Parkinson's. 

Another implication of the research is that the curli could be a target for attacking biofilms, a kind of goo created by bacteria, which acts as a shield to thwart antibiotics and antiseptics. These bacteria can cause chronic infections, but treating these infections using molecules that block curli formation may degrade the biofilm and leave the bacteria more vulnerable to drug therapy. 

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The study, "The bacterial curli system possesses a potent and selective inhibitor of amyloid formation," is scheduled to appear Jan. 22 in the online edition of Molecular Cell. 

Evans, who conducted the research while at U-M will be a postdoctoral fellow at Washington University in St. Louis. 

Other authors include: Fei Li of U-M Molecular, Cellular, and Developmental Biology; Erik Chorell, Jörgen Åden, Anna Göteson, Pernilla Wittung-Stafshede and Fredrik Almqvist of Umeå University; Jonathan Taylor, Marion Koch, Lea Sefer and Steve Matthews of Imperial College London. 

The work was funded in part by the National Institutes of Health. 

Margery Evans 
Matthew Chapman 
U-M Molecular, Cellular, and Developmental Biology

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

http://health.einnews.com/article/246050337/a5r9g7mw6bROANwA

Live Broadcast from Inside the Nerve Cell

 Neuroscience News

 January 23, 2015

For the first time, Max Planck researchers observe protein degradation in intact brain cells.

Scientists estimate that our brain consists of about ten to one hundred billions of nerve cells. In order to fulfill their respective tasks as long as possible, these cells have to constantly control their internal proteins with regard to quality and functionality. Otherwise the proteins might clump together and thereby paralyze or even kill the cells. Once the cell recognizes a defect protein, this is marked for degradation and a kind of a molecular shredder, the so-called proteasome, chops it into pieces that are eventually recycled.

For the first time now, researchers have succeeded in visualizing this process in intact nerve cells, which previously could only be investigated in the test tube. Electron cryo-tomography was essential for obtaining the described images. Hereby, cells are cooled down to minus 170°C in a fraction of a second. In a consecutive step, pictures of the interior of the cells are taken from many different angles, which then are merged computationally into a three-dimensional image.

“First time in intact cells”

The proteasomes (grey) of the nerve cell (neuron) are equipped with the regulatory particles at their ends. These structures change their shape depending on whether they have bound (red) proteins which have to be degraded (green) or not (blue). Image Credit: Shoh Asano/MPI of Biochemistry.

In the current study, the use of specific technical innovations allowed the researchers to achieve a unprecedented imaging quality, enabling them to distinguish single proteasomes within the cell. “For the first time it is possible to qualitatively and quantitatively describe this important enzyme complex in intact cells”, Asano classifies the results.

In the following experiments, the scientists focused on the activity of the proteasomes. For the interpretation of the single particles it is important to know that there are cap-like structures, the so-called regulatory particles, attached to the ends of proteasomes (see picture). They bind proteins that are designated to be degraded and thereby change their shape. The scientists were able to distinguish these states and consequently could deduce how many of the proteasomes were actively degrading proteins.

New prospects for the future

The conclusion of the researchers: in quiescent nerve cells like the ones used in the actual experiments, only a minority of the proteasomes is active. In detail, the results showed that only every fourth proteasome was actively degrading proteins while the rest idled at the same time. In the future, the scientists want to address the structural changes of the proteasomes under cellular stress as it occurs in neurodegenerative diseases. “This study shows the new possibilities to resolve protein complexes in their entirety in the cell and to study their mutual functional dependencies,” Wolfgang Baumeister, head of the study, determines the agenda for the future.

About this neuroscience research

Contact: Anja Konschak – Max Planck Institute
Source: Max Planck Institute press release
Image Source: The image is credited to Shoh Asano/MPI of Biochemistry and is adapted from the press release
Original Research: Abstract for “A molecular census of 26S proteasomes in intact neurons” by Shoh Asano, Yoshiyuki Fukuda, Florian Beck, Antje Aufderheide, Friedrich Förster, http://neurosciencenews.com/proteasome-protein-degradation-neurons-1734/ Danev, and Wolfgang Baumeister in Science. Published online January 23 2015 doi:10.1126/science.1261197

Ask the MD: What Is Orthostatic Hypotension?

FoxFeed Blog

Posted by  Rachel Dolhun, MD, January 22, 2015

Rachel Dolhun, MD, is a trained movement disorder specialist who works in medical communications at The Michael J. Fox Foundation. 

Orthostatic hypotension is a drop in blood pressure upon changing positions, such as moving from sitting to standing. It’s also a non-motor symptom of Parkinson’s disease. Orthostatic hypotension may cause lightheadedness and dizziness, which can result in passing out, fatigue and nausea. It could also contribute to gait instability and falls.

Low blood pressure has many possible causes beyond Parkinson’s disease. Dehydration could be the culprit, as well as many medications, including:

• high blood pressure medications,
• diuretics (fluid pills),
• antidepressants
• and many of the medications used to treat PD.

Other diseases, such as infection or anemia (low blood count), could also be to blame.

To look for orthostatic hypotension, doctors measure blood pressure while the patient is lying down, sitting and standing. Blood and/or urine tests may be performed to rule out other contributing factors.  

How Is Orthostatic Hypotension Treated?

Treatment depends on symptoms and the main reasons for low blood pressure. Your doctor may suggest dietary modifications, compression devices, adjustment strategies (described below) or medication changes.

If limited fluid intake is the problem — and you don’t have any heart or kidney problems —increased fluid and salt intake is usually recommended. Aim for five 8 ounce glasses of cold fluid – such as water, Gatorade, V8 juice — per half day. One way to ensure you drink enough is to fill a gallon container with fluid in the morning and empty from there throughout the day.

With regard to salt intake, table salt can be used liberally, and salty foods (canned soups, for example) can be added to meals. If that’s not to your taste, you might try over-the-counter salt tablets as directed by your physician. Caffeinated beverages, hot liquids and alcohol should be limited as they can lower blood pressure or worsen dehydration. Eating frequent, small meals and limiting carbohydrate intake will smooth blood pressure fluctuations, as well.

You may want to try lower extremity compression hose or abdominal binders to encourage normalization of blood pressure, but these are difficult to put on and can be uncomfortable.

• Other simple adjustments may have great benefit:
• Raise the head of the bed at night or use more pillows.
• Drink a full, cold glass of water prior to standing up.
• Change positions cautiously and slowly.
• Avoid prolonged standing, or shift positions/cross your legs if you do.
• Engage in regular physical exercise.

Another tactic your doctor may suggest is to alter your medication regimen. Initially this may be a decrease or discontinuation of high blood pressure medications or diuretics, or a switch in the formulation or dosage of Parkinson’s medications. If these are not effective or if blood pressure problems are particularly severe, your physician may prescribe a drug that elevates blood pressure. Options include midodrine, fludrocortisone, pyridostigmine and droxidopa.

NOTE: The medical information contained in this article is for general information purposes only. The Michael J. Fox Foundation has a policy of refraining from advocating, endorsing or promoting any drug therapy, course of treatment, or specific company or institution. It is crucial that care and treatment decisions related to Parkinson’s disease and any other medical condition be made in consultation with a physician or other qualified medical professional.

https://www.michaeljfox.org/foundation/news-detail.php?ask-the-md-what-is-orthostatic-hypotension

Researchers discover molecule that may lessen severity of Parkinson's disease

Jan. 17,2015

In normally functioning brain cells, mitochondria, or the ''powerhouses'' of cells, generate the energy needed to keep cells alive. When mitochondria become damaged and are no longer capable of making energy, they are sent to a portion of the cell called a lysosome to be repaired; however, in the brains of Parkinson's disease patients, mitochondria fail to move to lysosomes, causing accumulations of damaged mitochondria that kill brain cells.

Now, a University of Missouri (MU) researcher has found a molecule that could aid mitochondrial recycling and keep brain cells alive. The molecule could be key to developing drugs that will keep brain cells healthy in individuals with Parkinson's disease.

''Mitochondria eventually become damaged and no longer function properly, so the cell has a mechanism to recycle them, keeping them strong,'' says Mark Hannink, a professor in the Department of Biochemistry and an investigator at the Bond Life Sciences Center at MU.

He explains, ''In early onset Parkinson's, mutated proteins 'forget' to recycle mitochondria, resulting in a build-up of toxic waste and early onset of the disease. In our study, we found a peptide, or molecule, responsible for an alternative pathway that bypasses the mutant Parkinson's proteins and allows mitochondrial recycling. We feel that this peptide could prove useful in fighting diseases in the brain.''

This alternative pathway for mitochondrial recycling uses a protein called phosphoglycerate mutase family member 5 (PGAM5). In Hannink's study, he discovered a peptide which acts as a ''switch'' to cause the protein to create an alternate pathway. By regulating the protein with the peptide he discovered, it may be possible to restore mitochondrial recycling in neurons of patients with Parkinson's, lessening the severity of the disease.

''Peptides behave like drug molecules,'' Hannink says. ''Any time you can identify a biological process that is regulated by a peptide, that peptide becomes a leading candidate in the search for small, drug-like molecules that will act the same way.''

For Parkinson's disease, the goal is to find ways to repair the mitochondria recycling process. The next step of his research is to produce a drug molecule that can regulate the PGAM5 protein in cells, just as the peptide did in his experiments, Hannink said.

The early-stage results of this research are promising. If additional studies are successful within the next few years, MU officials will request authority from the federal government to begin human drug development (this is commonly referred to as the ''investigative new drug'' status). After this status has been granted, researchers may conduct human clinical trials with the hope of developing new treatments for Parkinson's and other diseases.

Hannink's study, A conserved motif mediates both multimer formulation and allosteric activation of phosphoglycerate mutase 5, recently was published in the Journal of Biological Chemistry. Peter Tipton, professor of biochemistry, and graduate students Jordan M. Wilkins and Cyrus McConnell contributed to the research.

-       See more at: http://www.domain-b.com/technology/Health_Medicine/20150117_parkinson.html#sthash.M6Hdr4dK.dpuf

http://www.domain-b.com/technology/Health_Medicine/20150117_parkinson.html

New Parkinson's Treatment on Two Wheels

July 20, 2009 

By CATHY BECKER via 

Neuroscientist Jay Alberts is an avid cyclist, but he never expected to make any medical discoveries on his bike. He did just that on a 50-mile ride across Iowa with his tandem bike partner, fellow neurologist Dr. David Heydrick, who has the movement disorder known as Parkinson's disease. 

ABC News

Neuroscientist Jay Alberts is an avid cyclist, but he never expected to make any medical discoveries on his bike.

He did just that on a 50-mile ride across Iowa with his tandem bike partner, fellow neurologist Dr. David Heydrick, who has the movement disorder known as Parkinson's disease.

After the bike trip, Heydrick noticed that his handwriting dramatically improved.

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In a video they shot before the ride, Heydrick's hand shook wildly, but afterward, it was steady.

In Alberts' mind, the mysterious side effect of the bike ride held an intriguing medical possibility that motor control in the arms could improve even if it was the legs that were exercising.

"It suggested that there was some change in the central nervous system or the brain function," Alberts told "Good Morning America." "What we were thinking was, maybe we have found a method of exercise here that actually is treating the disease rather than just treating some of the symptoms."

To find out, Alberts started a small trial at the Cleveland Clinic in Cleveland, Ohio, to test whether eight weeks of forced exercise on a tandem bike could improve the symptoms of Parkinson's disease. Forced exercise requires the patient to peddle faster than they would voluntarily.

"What we found was there was a 35 percent improvement in motor functioning for those patients who did the forced exercise compared to the voluntary exercise," Alberts said.

According to Alberts, the improvement lasted, although dwindled, for four weeks after the patients stopped biking.

Current Parkinson's medications generally control only motor functions for a few hours, much less days. Patient Sally Terrell said all the exercise was worth it.

"I noticed that after continued exercise that I have a calmer right side," Terrell said.

Scientists: Exercise Could Be Overriding Nervous System

Researchers think the forced exercise works because making people peddle harder may be overdriving the central nervous system, triggering the release of some chemicals that may improve motor function.

"Maybe we can turn back the clock and improve motor function to earlier levels of diagnosis," Alberts said.

Following the study, Alberts contacted Dr. Micheal Phillips for a brain scan study, comparing the brain of a Parkinson's patient on medication for the disease and one who has exercised. In each, the same brain regions were activated.

"You know, the hope is that you have an alternative way to treat your Parkinson's disease," Phillips said. "This is really cool stuff."

Terrell was so convinced of the workout's effectiveness that she has continued to exercise to battle the disease.

"I have seen the results, and I'm looking forward to keeping this disease at bay as best I can," she said.

Dance companies are getting involved in fighting the disease as well. The Mark Morris Dance Group in New York City offers classes for people suffering with Parkinson's, saying that it improves flexibility and instills confidence.

Scientists said it would take more studies to conclude if exercise actually slowed down the progression of Parkinson's and whether it could complement or even replace medication.

http://abcnews.go.com/GMA/OnCall/parkinsons-treatment-wheels/story?id=8109965

University of Missouri Discovery May Aid Parkinson’s Fight

Tuesday January 20, 2015

Kyle Loethen

Missourinet - University of Missouri researchers might have found a way to lessen the severity of Parkinson’s disease.

Department of Biochemistry Professor Mark Hannink

Researchers have discovered a molecule that could be key to developing drugs that will keep brain cells healthy in individuals with Parkinson’s.

Mitochondria generate the energy needed to keep brain cells alive.  When mitochondria become damaged and are no longer capable of making energy, they are sent to a part of the cell called a lysosome to be repaired.  For those suffering from Parkinson’s disease, mitochondria fail to move to lysosomes, causing buildups of damaged mitochondria that kill brain cells.

Department of Biochemistry professor Mark Hannink says the goal is to prevent the cells from dying.

“We think we know what causes the cells to die and that’s failure to recycle the mitochondria,” said Hannink.  “So, what we think we’ve found is an alternative way to promote the getting rid of damaged mitochondria.”

The alternative pathway for mitochondrial recycling uses a protein called phosphoglycerate mutase family member 5 (PGAM5).  Hannink’s study found a peptide which acts as a “switch” to cause the protein to generate an alternate pathway.  By regulating the protein with the peptide he discovered, it could be possible to restore mitochondrial recycling in neurons of patients with Parkinson’s.

Hannink says most of the published work has been test tube based.

“That’s really the foundation of drug development.  Drugs are small molecules, but are designed then to interact in very specific ways with particular regions on proteins and change their function,” said Hannink.

Hannink says after they characterize how the molecule behaves against purified protein and against mitochondria in cultured cells, they will begin testing on mice.

“There’s a couple of researchers in the school of medicine who have mouse models of Parkinson’s disease.  We’ll be collaborating with them to do those tests,” said Hannink.

With the hope of developing new treatments for Parkinson’s, University of Missouri officials may request authority from the federal government to conduct human clinical trials if these additional studies are proven to be successful.

http://www.missourinet.com/2015/01/20/missouri-researchers-discover-molecule-that-may-aid-parkinsons-disease/

https://nwpf.org/stay-informed/news/2015/01/university-of-missouri-discovery-may-aid-parkinson’s-fight/

Stepping Out

Just a picture of regular shoes
Not PD shoes

Thursday January 15, 2015

Margie Fishman

Delaware Online: The News Journal - Parkinson's robbed Ed Slygh of the ability to walk without fear.

Diagnosed in 2009, the Vietnam War veteran believes he developed the degenerative disorder of the nervous system after being exposed to Agent Orange during his military service. He now shuffles around with rounded shoulders.

Since testing a vibrating beach shoe developed at UD, the Lewes retiree is having an easier time navigating sharp turns and can take larger steps without freezing in place. While walking around the mall, he surprised himself by picking up his cane and twirling it.

"The most exciting thing for me is that it's not invasive," says Slygh, who admits that the shoe tickles a bit.

Nearly 1 million Americans live with Parkinson's disease. Actor Michael J. Fox's foundation has directed funding toward finding a cure. The foundation recently partnered with Intel Corp. on a device to help Parkinson's patients track symptoms.

Closer to home, UD researchers have spent the last few years developing a flexible, rubberized shoe to help individuals with Parkinson's walk steadier.

While a healthy person takes one step about every 1.15 seconds, individuals with Parkinson's can take 1.35 seconds per step. That might seem like a minuscule difference, but those longer steps slow down a person's gait.

Directing the UD research is Ingrid Pretzer-Aboff, an associate nursing professor at UD with 30 years of experience treating people with Parkinson's. Kyle Winfree, a postdoctoral researcher in biomechanics, built the shoe. Researchers selected a water shoe because it was inexpensive and came in standard sizes.

Operated by a microcomputer, the "shoe" is really a vibrating insole that can store data. It measures the duration of each step – when the heel strikes the ground and rolls forward onto the ball of the foot.

Participants from India and the U.S. tested the shoe twice a day at six-minute intervals for two weeks. They generally reported smoother walking, better balance and faster walking pace, Pretzer-Aboff says. These benefits were particularly pronounced for those who had advanced Parkinson's.

Those findings, gathered over three pilot studies, support earlier research by 19th-century French neurologist Jean-Martin Charcot. Charcot found that people with poor motor control benefited from long train or carriage rides. He created a vibration chair as a form of treatment, but died before it could be tested.

So far, about 150 participants have tested the continuously vibrating shoe, called the PDShoe, and an earlier version that delivered step-synchronized vibrations.

Researchers are still trying to determine why the vibrations work so well. Is it because the muscle gets so excited from the vibration that it is more receptive to the signal from the brain telling it to move? Or does the vibration simply act as a tactile cue?

Whatever the mechanism, the shoe successfully bridges engineering and human health and boosts the self-esteem of the wearer, according to Pretzer-Aboff.

"Imagine if you got your feet back," she says.

http://www.delawareonline.com/story/life/2015/01/15/wearable-tech-supporting-limbs-easing-parkinsons/21826073/

https://nwpf.org/stay-informed/news/2015/01/stepping-out/

Portable stimulator being tested on Parkinson's patients

PUBLIC RELEASE: 20-JAN-2015

UNIVERSITY OF GOTHENBURG

IMAGE: THIS IS FILIP BERGQUIST FROM THE INSTITUTE OF NEUROSCIENCE AND PHYSIOLOGY, SAHLGRENSKA ACADEMY, UNIVERSITY OF GOTHENBURG

Parkinson's disease is a slowly degenerative neurological disease that is expressed as impaired motor control, tremors, stiffness and, in later stages, problems with balance.

The symptoms are caused by a lack of the signal substance dopamine and is traditionally treated with medication. However, balance problems do usually not improve much with pharmacological treatment.

Change brain activity

In earlier experiments on rats, researchers at the Sahlgrenska Academy showed that noisy electric stimulation of the balance organs can be used to change the activity of the brain, thereby balancing the effects of dopamine shortage and improve the animals' motor skills and balance.

The researchers have now tested the same method on ten Swedish Parkinson's patients.

Improved balance

The patients were studied in both medicated and unmedicated states. On one day, the patients received an active noise stimulation and on another day inactive treatment, blinded to which day the current was active. The experiments show that the active noise stimulation improved both the patients' balance and the combined symptoms.

"The effect on balance was particularly apparent when the patients were in the unmedicated state, which is very positive," says Associate Professor Filip Bergquist at the Sahlgrenska Academy who led the study.

Pocket stimulator

In a follow-up study over a longer time, the researchers will now have the Parkinson's patients wear a stimulator that is smaller than a wallet and can be carried in the pocket.

"If the long-term treatment improves the patients' walking, balance and symptom variations, we could in the next five years develop the noise stimulation technique and introduce it as a new treatment," says Filip Bergquist.

The current study is published in the scientific journal Brain Stimulation and was conducted in cooperation with researchers at NASA, who also helped with technical equipment.

The article Effects of Stochastic Vestibular Galvanic Stimulation and LDOPA on Balance and Motor Symptoms in Patients With Parkinson's Disease was published online in Brain Stimulation on January 5.

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Link to abstract:  http://www.brainstimjrnl.com/article/S1935-861X%2814%2900398-2/abstract

Contact: 
Filip Bergquist, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg 
+46-702 223 664 

http://health.einnews.com/article/245372765/ZQuy1QwoHJTqpGm1

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

25 Things People with Parkinson's Disease Can Relate To

FoxFeed Blog

Posted by  Allison Smith, January 16, 2015

Guest blogger Allison Smith describes herself this way: "I am a medical anomaly, advocate for people, freakishly smart, believer of unicorns, self-proclaimed addict of frozen yogurt, secretly a ninja, and personally planning the assassination of Barbie...Oh and I have Parkinson's disease. If I could describe myself in one sentence, I wouldn't be blogging!" Find more of her entertaining posts at The Perky Parkie.

Now readers, before I get started, I want to remind you that my blog is strictly for entertainment purposes and is not meant to diagnosis or treat any medical illness.  I am not a doctor, and although I am freakishly smart, you should probably follow-up with someone a little more serious than myself.

1. Being frozen does not necessarily mean that you are cold.

2. You know that if you are seeing unicorns and believe that your car is made out of skittles, you’re probably taking a dopamine agonist.

3. You can play the fun game of, “What symptoms will I have today?”

4. At the grocery store staring at the gum, you take 20 minutes to pick a flavor, only to return moments later to exchange it.

5. You start 10 projects at home and haven’t finished one.

6. Everyday you’ll have to eat candy, or someone will get hurt.

7. You’ll wear a mask, even if it’s not Halloween.

8. You have hidden stashes of Sinemet in your purse, gym bag, key chain, glove box, wallet, and in the flowerpot on your patio.

9. You do a perfect imitation of a garden statue.

10. You can cry almost on cue.

11. You have perfected the dance move called Dyskinesia.

12. You stayed up all night organizing your family photos, and then decide to clean out the garage.

13. Multi-tasking sounds like too much work, so you don’t do it.

14. It doesn’t matter how cold it is, you are somehow sweating.

15. Shaving can be hazardous to your health.

16. When you walk, one arm goes on strike and decides not to swing.

17. No, you don’t smell the dog poo you just stepped in.

18. You will never need to buy an electric toothbrush every again.

19. Your ability to balance decided to take a vacation to Fiji and hasn’t even sent a postcard.

20. You know that Dystonia is not a city in Estonia.

21. You will always win a staring contest.

22. You have been pulled over for drunk driving, but haven’t even had a drop of booze.

23. You know that an abduction by aliens in not necessary to get Deep Brain Stimulation.

24. You would pay top dollar for Dopamine on the black market.

25. Bloodhounds are jealous of your ability to drool.