Calcium channels team up to activate excitable cells

May 20, 2016

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            Finding contradicts earlier belief that channels do not work cooperatively.

Voltage-gated calcium channels open in unison, rather than independently, to allow calcium ions into and activate excitable cells such as neurons and muscle cells, researchers with UC Davis Health System and the University of Washington have found.

The research defies earlier electrophysiology canon and undermines the previously held belief that calcium channels function independently. The study is published online in the journal eLIFE.

The finding is important, the researchers said, because understanding how these channels collaborate could lead to improved therapies that target aberrant calcium channels in malfunctioning cells. Dysfunctional calcium channels can be found in a variety of conditions, such as epilepsy and Parkinson's disease.

"In cardiac muscle, if these channels don't coordinate their firing, it will have detrimental repercussions on the reliability of the cardiac muscle contractions," said Luis Fernando Santana, professor and chair of the Department of Physiology and Membrane Biology at UC Davis. "In neurons, if they don't gang up, they don't get the potentiation they need to sustain repetitive firing.

"In a previous study we found that a bad channel paired with a good channel can turn both of them bad," Santana said. "So, you don't need a lot of bad channels to make a cell dysfunctional and show pathological behavior."

To study these tiny channels, the researchers used high-resolution microscopy, electrophysiological measurements and optogenetic technologies - light-sensitive probes that can stimulate neurons to fire electrical signals - to study rat hippocampal neurons. They found that when cells begin responding to calcium, channels start grouping in clusters of two or more and open cooperatively, allowing cells to fire more rapidly.

"This is a clear demonstration that voltage-gated calcium channels can couple to amplify the influx of calcium and control a cell's excitability," Santana added. "This coordination has a powerful influence on the behavior of neurons and other excitable cells."

The channels coordinate through a protein called calmodulin, which binds to calcium and helps carry it through the channel.

"Normally these channels don't touch each other," Santana said. "However, a little bit of calcium comes through and calmodulin serves as a bridge between neighboring channels. Influenced by the channel that opens first, they begin opening in unison, bringing channels together."

The researchers also found that these clusters dissolve much more slowly than the associated calcium. This "molecular memory" may allow cells to anticipate future firings, increasing their efficiency.

"It's always been a contradiction," noted Santana. "In a heart muscle, five to 10 channels have to open to activate calcium release reliably during the activation of contraction, but the chance of such a cluster of channels firing simultaneously is minuscule unless there is some cooperation."

This research was funded by the National Heart, Lung, and Blood Institute (HL085870 and HL085686); National Institute of Neurological Disorders and Stroke (NS077863); and American Heart Association (15SDG25560035).

Article: Ca2+ entry into neurons is facilitated by cooperative gating of clustered CaV1.3 channels, Claudia M Moreno, Rose E Dixon, Sendoa Tajada, Can Yuan, Ximena Opitz-Araya, Marc D Binder, Luis F Santana, eLIFE, doi: 10.7554/eLife.15744, published 17 May 2016.

http://www.medicalnewstoday.com/releases/310434.php

Aging in the Key of Humor

Timothy Egan

May 20, 2016

His back hurts. His memory is slipping. He can’t cook, but then he never could. Igloo-making is no longer one of his diversions. The wit is sharp, quick as ever, but now he’s prone to … what’s the word? Oh, and he has Parkinson’s disease.

Michael Kinsley is aging so you don’t have to. The editor in him, the one who held the reins at The New Republic, Harper’s and Slate, and grasped for a few hours the chance to helm The New Yorker, would refine that. Here’s how he puts it, in his guidance to the 74 million baby boomers entering the years of living less dangerously:

“But when it comes to the ultimate boomer game, competitive longevity, I’m on the sidelines doing color commentary.” His chronic disease, which gives him many of the symptoms of old age but which he believes is no more likely to bring him to an early death than slipping on a bar of soap, has presented him with “an interesting foretaste of our shared future.”

Kinsley, who coined a new definition of a gaffe — when a politician tells the truth — and once described 38-year-old Al Gore as “an old person’s idea of a young person,” (today, Paul Ryan), is in public service mode, out with a slim book on aging. “Sometimes I feel like a scout from my generation, sent out ahead to experience in my 50s what even the healthiest boomers are going to experience in their 60s, 70s and 80s.”

Full disclosure: I like Kinsley. I would call him a friend, even if his trademark misanthropy prevents him from returning the sentiment. But here’s the thing: I loathe books about baby boomers. I hated the yuppie thing. I despised the era when my generation acted as if we were the first people ever to have kids. And I can’t stand the Viagra-taking, booty-shaking, aging rocker phase. I don’t doubt that boomers will “reinvent” old age, because that’s what boomers do to every age.

But along the road to Bernie Sanders grumpiness, can somebody slap some sense into these people? Enter Kinsley. At age 65, his Parkinson’s has given him a premature taste of the stumbling, the cognitive slips, the limits that will inevitably define life’s actuarial last trimester. He can no longer drive. A woman at a dinner party offered to cut up his meat.

When I met Kinsley in 1996, he had just moved to Seattle to start Slate, the online magazine. There were many reasons to hate him: Harvard graduate, Rhodes Scholar, wunderkind editor, talking head on CNN’s “Crossfire,” his visage on the cover of Newsweek, under the headline: “Swimming to Seattle: Everyone Else is Moving There. Should You?”

I gave him six months before he left. Surely he would die outside the biosphere of Beltway bloviation. A decade later, he was still here in Seattle. He found true love, his wife Patty Stonesifer — who has done much good in nonprofits and philanthropy after doing well at Microsoft. I always thought of him as a highly evolved brain inhabiting an uncertain body, an E.T. with wit. But then he learned to backpack in the Cascade Mountains, to snowshoe, to swim in Lake Washington in winter, and yes, to build an igloo — all with Parkinson’s, which was diagnosed when he was 43.

In his book, “Old Age — A Beginner’s Guide,” he tries on altruism, suggesting that boomers’ ultimate gift to the future would be to pay off the national debt, and do it before the last of that g-g-generation turns 65, in 2029.

Nice try. Never going to happen. Kinsley’s contribution to the wave of new books, shows and miracle antidotes to aging is his approach. Where others would groan, wince, cry or whine, Kinsley is looking for the joke. So, after undergoing nine hours of deep brain surgery, he thought of what he could say to assure his friends he had not lost any of his analytical skills.

“Well, of course,” he said, post-op. “When you cut taxes, government revenues go up. Why couldn’t I see that before?”

Easy for him to say. No, actually, it’s not. His Parkinson’s meds allow him to seem relatively symptom-free for hours, but then he starts to stiffen, like the Tin Man in “The Wizard of Oz,” in need of oil. And Kinsley admits to some loss of his mental acuity in recent years.

He notes that 28 million boomers are expected to develop Alzheimer’s or some other form of dementia — nothing to laugh at. “Dementia seems like an especially humiliating last stop on the road of life,” Kinsley writes. “There’s no way to do it in style or in dignity.”

But perhaps there’s a way to find some grace notes through humor. I saw Kinsley this week, before a packed house at Seattle’s Town Hall. He was in typical form. Asked at the end of the evening what his audience should “take away” from the distilled wisdom of his book, he paused, giving that owlish, quizzical look of his and said, “Several copies.”

http://www.nytimes.com/2016/05/20/opinion/aging-in-the-key-of-humor.html?_r=0

Parkinson's News Today Researchers Develop and Share 10 Stem Cell Lines with Common Parkinson's Mutations

Margarida Azevedo

MAY 20, 2016

Scientists at the Buck Institute for Research on Aging have derived 10 induced pluripotent stem cells (iPSC) lines from Parkinson’s disease (PD) patients that carry the most common mutations associated with the disease. These cell lines and related genomic information will be made available to the larger scientific community, and PD models created using them may help to further understanding of the disease’s underlying causes, and to discover new diagnostic biomarkers and therapeutic drugs.

The cell lines are in the process of being deposited at a facility approved by the U.S. National Institutes of Health (NIH).

PD, a progressive and neurodegenerative disease, is characterized by the loss of control of balance, movement, and coordination, as well as a higher risk of dementia. While some patients have a family history of the disease, most cases are not inherited. Scientists believe the underlying causes of PD stem from a combination of genetic, environmental, and epigenetic factors, but questions remain.  According to the National Parkinson Foundation, about 10% to 15% of Parkinson’s cases are thought to derive from mutations in specific genes, such as LRRK2, PARK2 and GBA.

Researchers, led by Xianmin Zeng, PhD, derived iPSC lines from skin cells donated by PD patients carrying the mutations SNCA, LRRK2, PARK2 and GBA. These cells were them reprogrammed to exhibit embryonic stem cell behavior, and induced to differentiate into dopaminergic neurons, the cells affected in PD. At each stage of the process, the scientists performed whole genome expression analysis.

“This work combined with dozens of other control, isogenic and reporter iPSC lines developed by Dr. Zeng, will enable researchers to model PD in a dish,” Dr. Brian Kennedy, Buck Institute president and CEO, said in a news release. “Her work, which we are extremely proud of, will help researchers dissect how genes interact with each other to cause PD, and assist scientists to better understand what experimental drugs are doing at the molecular level to decide what drugs to use based on mutations.”

A need exists for new and accurate PD models, since neurons obtained from patients have limited value, and animal models inadequately represent the human disease process.

“We think this is the largest collection of patient-derived lines generated at an academic institute,” said Dr.  Zeng, who is working on a stem cell replacement therapy for PD. “We believe the lines and the datasets we have generated from them will be a valuable resource for use in modeling PD and for the development of new therapeutics.”

The research article, “Derivation, Characterization, and Neural Differentiation of Integration-Free Induced Pluripotent Stem Cell Lines from Parkinson’s Disease Patients Carrying SNCA, LRRK2, PARK2, and GBA Mutations,” was published in PLOS One.

The Buck Institute, a nonprofit and independent biomedical research center, is based in Novato, California.

http://parkinsonsnewstoday.com/2016/05/20/buck-research-may-provide-missing-link-search-parkinsons-disease-therapeutics/

Denise Wallace lives life with Parkinson’s while educating others

By VALERIE BUCCIO 

Denise Wallace, 59, had awake brain surgery to have a deep brain stimulator device implanted in her brain that leads down to a battery in her chest. The device helps control Parkinson's disease symptoms.

Thursday, May 19, 2016 

HICKORY — Denise Wallace was driving down the highway when the left side of her body went completely numb. Her initial thought was a stroke. However, after arriving at the Emergency Room (ER), doctors told her that was not the case.

“I have Parkinson’s, but Parkinson’s does not have me,” Wallace said.

Wallace, 59, has had Parkinson’s disease for 17 years, if not more, because she was misdiagnosed for eight years.

After seeing five neurologists, they told her she had MS when she was 42 years old. She was diagnosed with Parkinson's disease when she was 50 years old.

For five years, she was on steroids for MS that gave her several side effects and made her feel poorly. The steroids did nothing to help her, she added.

Eventually she saw a doctor from Johns Hopkins Hospital who decided to throw out everything they have done so far and started with a clean slate, Wallace said.

The doctor gave Wallace Parkinson’s disease medicine, and after two days, she went from a wheelchair to walking.

“It blew my mind,” Wallace said.

After seeing the Johns Hopkins doctor for several years, she switched to a doctor at Duke Hospital. He recommended Wallace get a Medtronic deep brain stimulator (DBS) device, a pacemaker for the brain, she added.

The DBS has two leads implanted in the brain that are attached to a neurostimulator near the collarbone, Wallace said. Inside the neurostimulator is a battery and a chip that sends electrical pulses to help control Parkinson’s disease symptoms.

Wallace said her first awake brain surgery was eight years ago. She had a second surgery a year ago.

“You hear them drilling, cracking the bone and you don’t feel it, you don’t feel a thing,” Wallace said. “Isn’t that wild?”

During the surgery, she was awake in order for the surgeon to hear her speak and ask her to do small movements to make sure nothing was tweaked during the procedure, Wallace said.

Once she arrived home after the surgery, she had a seizure, Wallace said. During the seizure, she bit her tongue and bled all over her pillow.

Although she couldn’t drive and was on a certain medication for a month, that was the only episode. No more seizures or complications came.

Two weeks after the surgery, the DBS turned on and she went from shaking to steady immediately.

Seven years after the initial surgery, the DBS stopped working because an electrode from the device in her brain had a shortage that needed replacing, she said.

“I’d be walking then I’d stop, I’d get frozen,” Wallace said.

At age 58, she had a second awake brain surgery to fix the electrode.

“I knew immediately after I had the surgery that something was not right,” she said.

One of the leads in her brain moved 1 millimeter, which they knew was a possible risk, Wallace said.

“It’s one of those things where they told you there were risks, you can do it and it may make you better or you can do it and it may make it worse, it’s like what do you do?” Catawba Valley Medical Center (CVMC) Physical Therapist Caroline Windham said.

Wallace said she takes more Sinemet, Parkinson medicine, to compensate for the lead moving and electrodes not working correctly. More medicine means more shaking than usual though, she added.

“I’m like a rollercoaster all day,” Wallace said. “It’s up and down all day, and it makes me so mad.”

Parkinson’s disease causes no production of dopamine, which helps walking and function, so the medicine replaces the dopamine, Wallace said.

Wallace is on the list to see a specialist from the University of Florida. The specialist had her records for five months before deciding to accept her into the program.

“This guy in Florida is world renowned, and I’ll do what he says,” Wallace said. “If I have to rent an apartment down there to stay, I’ll do it.”

Between the ages of 15 and 22 years old, Wallace had 26 surgical OBGYN procedures due to several medical conditions.

“I’m wondering if being put to sleep so many times had anything to do with (having Parkinson’s),” Wallace said.

Therapy

Wallace joined the BIG & LOUD Therapy Program at CVMC with Windham at the end of 2014, Wallace said.

The program is four days a week for four weeks including techniques to help patients’ range of movement, Windham said.

BIG & LOUD was made for people with Parkinson’s disease, Windham said. Anyone with movement disorders or speech impediments will benefit from the program though.

Parkinson’s disease comes in five stages: 0 being no sign of disease and 5 being wheelchair or bedridden, Windham said.

“The bigger they move, the more normal it looks for Parkinson’s disease patients,” Windham said.

They do standing, walking, sitting, twisting, and reaching movements during the therapy sessions, Windham said.

“When I’m walking, I can just say ‘big steps,’ I think about it,” Wallace said.

To patients the movements feel huge, and the goal is to find a norm for each individual.

“If they learn the techniques early and how to move, they hopefully can apply them long-term,” Windham said.

At the beginning of therapy, Wallace was doing the Parkinson’s shuffle where she would shuffle her feet when walking instead of taking strides, she said. By the end, she was walking normal with no cane assistance.

“I did remarkably,” Wallace said.

The third week of the program, Wallace did a 5K for National Parkinson’s Foundation with her whole family.

“You got to have a positive attitude, a support system and a lot of oomph,” Wallace said.

Her family has been a support system she is grateful for, Wallace said. Her husband, Dan Wallace, her daughter, Kimberly Wallace, her son-in-law, Joe Repaire, and her grandson, Graham Repaire told her from the beginning they would do what they can to help and they have.

Shortly after she graduated from the program, she had the second brain surgery that required six months of recovery, Wallace said.

Wallace wasn’t able to do the BIG therapy program again due to her condition after the brain surgery, she said. She got back to walking, but not to the extent of before, she added.

Wallace recently finished eight weeks of therapy. She will go on sabbatical and then return.

She now goes in for small tune-ups instead of the full program because she is doing so well.

Wallace also has small daily homework assignments from Windham.

“Sometimes I can do it, some days I can’t, but I religiously try every day,” Wallace said.

Educating the community

Throughout this process, Wallace hasn’t let Parkinson’s stop her from living.

She has done yoga for 15 years and continues to do it every week, she said. The days she doesn’t do yoga, she uses exercise machines.

“I do Yoga three times a week, I’ve done it for 15 years and that’s a godsend,” Wallace said. “I do it religiously, you cannot stop me.”

Wallace strives for people like her or people with movement disorders to stay active and keep fighting.

She wants to implement Rock Steady Boxing at the fitness center at CVMC. Parkinson’s patients would do it three times a week and improve physically and mentally, she said.

A few concerns are not having enough people participate, but Wallace said, “You get it, they’ll come.”

Along with trying to find new classes and therapy for people with Parkinson’s, Wallace speaks at churches and other events on a National level as the Ambassador of Michael J. Fox Foundation.

“If I can talk, I’m going to do it,” Wallace said.

She has talked with hundreds of people about the deep brain surgery to help people decide whether to do it or not since she has experienced it twice firsthand.

“God has a plan for all of us, and mine is to educate people,” Wallace said.

http://www.hickoryrecord.com/news/denise-wallace-lives-life-with-parkinson-s-while-educating-others/article_9dd8094c-1e0b-11e6-99e8-e3a1f71e5bde.html

Electronic device detects molecules linked to cancer, Alzheimer's and Parkinson's

May 19, 2016

AN INEXPENSIVE PORTABLE BIOSENSOR HAS BEEN DEVELOPED BY RESEARCHERS AT BRAZIL'S NATIONAL NANOTECHNOLOGY LABORATORY WITH FAPESP'S SUPPORT.
A biosensor developed by researchers at the National Nanotechnology Laboratory (LNNano) in Campinas, São Paulo State, Brazil, has been proven capable of detecting molecules associated with neurodegenerative diseases and some types of cancer.

The device is basically a single-layer organic nanometer-scale transistor on a glass slide. It contains the reduced form of the peptide glutathione (GSH), which reacts in a specific way when it comes into contact with the enzyme glutathione S-transferase (GST), linked to Parkinson's, Alzheimer's and breast cancer, among other diseases. The GSH-GST reaction is detected by the transistor, which can be used for diagnostic purposes.

The project focuses on the development of point-of-care devices by researchers in a range of knowledge areas, using functional materials to produce simple sensors and microfluidic systems for rapid diagnosis.

"Platforms like this one can be deployed to diagnose complex diseases quickly, safely and relatively cheaply, using nanometer-scale systems to identify molecules of interest in the material analyzed," explained Carlos Cesar Bof Bufon, Head of LNNano's Functional Devices & Systems Lab (DSF) and a member of the research team for the project, whose principal investigator is Lauro Kubota, a professor at the University of Campinas's Chemistry Institute (IQ-UNICAMP). 

In addition to portability and low cost, the advantages of the nanometric biosensor include its sensitivity in detecting molecules, according to Bufon.

"This is the first time organic transistor technology has been used in detecting the pair GSH-GST, which is important in diagnosing degenerative diseases, for example," he explained. "The device can detect such molecules even when they're present at very low levels in the examined material, thanks to its nanometric sensitivity." A nanometer (nm) is one billionth of a meter (10-9 meter), or one millionth of a millimeter.

The system can be adapted to detect other substances, such as molecules linked to different diseases and elements present in contaminated material, among other applications. This requires replacing the molecules in the sensor with others that react with the chemicals targeted by the test, which are known as analytes.

The team is working on paper-based biosensors to lower the cost even further and to improve portability and facilitate fabrication as well as disposal.

The challenge is that paper is an insulator in its usual form. Bufon has developed a technique to make paper conductive and capable of transporting sensing data by impregnating cellulose fibers with polymers that have conductive properties.

The technique is based on in situ synthesis of conductive polymers. For the polymers not to remain trapped on the surface of the paper, they have to be synthesized inside and between the pores of the cellulose fibers. This is done by gas-phase chemical polymerization: a liquid oxidant is infiltrated into the paper, which is then exposed to monomers in the gas phase. A monomer is a molecule of low molecular weight capable of reacting with identical or different molecules of low molecular weight to form a polymer. 

The monomers evaporate under the paper and penetrate the pores of the fibers at the submicrometer scale. Inside the pores, they blend with the oxidant and begin the polymerization process right there, impregnating the entire material.

The polymerized paper acquires the conductive properties of the polymers. This conductivity can be adjusted by manipulating the element embedded in the cellulose fibers, depending on the application for which the paper is designed. Thus, the device can be electrically conductive, allowing current to flow without significant losses, or semiconductive, interacting with specific molecules and functioning as a physical, chemical or electrochemical sensor.

http://www.eurekalert.org/pub_releases/2016-05/fda-edd051916.php?