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  • richardmitnick 12:29 pm on May 31, 2017 Permalink | Reply
    Tags: , , Human embryonic stem (ES) cells, , , Parkinson’s disease,   

    From Nature: “Trials of embryonic stem cells to launch in China” 

    Nature Mag

    31 May 2017
    David Cyranoski

    Former Chinese leader Deng Xiaoping had Parkinson’s disease, one of the first targets of embryonic-stem-cell therapies being tested in China.

    In the next few months, surgeons in the Chinese city of Zhengzhou will carefully drill through the skulls of people with Parkinson’s disease and inject 4 million immature neurons derived from human embryonic stem cells into their brains. Then they will patch the patients up, send them home and wait.

    This will mark the start of the first clinical trial in China using human embryonic stem (ES) cells, and the first one worldwide aimed at treating Parkinson’s disease using ES cells from fertilized embryos. In a second trial starting around the same time, a different team in Zhengzhou will use ES cells to target vision loss caused by age-related macular degeneration.

    The experiments will also represent the first clinical trials of ES cells under regulations that China adopted in 2015, in an attempt to ensure the ethical and safe use of stem cells in the clinic. China previously had no clear regulatory framework, and many companies had used that gap as an excuse to market unproven stem-cell treatments.

    “It will be a major new direction for China,” says Pei Xuetao, a stem-cell scientist at the Beijing Institute of Transfusion Medicine who is on the central-government committee that approved the trials. Other researchers who work on Parkinson’s disease, however, worry that the trials might be misguided.

    Both studies will take place at the First Affiliated Hospital of Zhengzhou University in Henan province. In the first, surgeons will inject ES-cell-derived neuronal-precursor cells into the brains of individuals with Parkinson’s disease. The only previous trial using ES cells to treat Parkinson’s began last year in Australia; participants there received stem cells from parthenogenetic embryos — unfertilized eggs that are triggered in the lab to start embryonic development.

    In the other Zhengzhou trial, surgeons will take retinal cells derived from ES cells and transplant them into the eyes of people with age-related macular degeneration. The team will follow a similar procedure to that of previous ES-cell trials carried out by researchers in the United States and South Korea.

    Qi Zhou, a stem-cell specialist at the Chinese Academy of Sciences Institute of Zoology in Beijing, is leading both efforts. For the Parkinson’s trial, his team assessed hundreds of candidates and have so far have picked ten who best match the ES cells in the cell bank, to reduce the risk of the patients’ bodies rejecting the cells.

    The 2015 regulations state that hospitals planning to carry out stem-cell clinical work must use government-certified ES-cell lines and pass hospital-review procedures. Zhou’s team completed four years of work with a monkey model of Parkinson’s, and has met the government requirements, he says.

    Parkinson’s disease is caused by a deficit in dopamine produced by brain cells. Zhou’s team will coax ES cells to develop into precursors to neurons, and will then inject them into the striatum, a central region of the brain implicated in the disease.

    In their unpublished study of 15 monkeys, the researchers did not observe any improvements in movement at first, says Zhou. But at the end of the first year, the team examined the brains of half the monkeys and found that the stem cells had turned into dopamine-releasing cells. He says that they saw 50% improvement in the remaining monkeys over the next several years. “We have all the imaging data, behavioural data and molecular data to support efficacy,” he says. They are preparing a publication, but Zhou says that they wanted to collect a full five years’ worth of animal data.

    Maturity concerns

    Jeanne Loring, a stem-cell biologist at the Scripps Research Institute in La Jolla, California, who is also planning stem-cell trials for Parkinson’s, is concerned that the Australian and Chinese trials use neural precursors and not ES-cell-derived cells that have fully committed to becoming dopamine-producing cells. Precursor cells can turn into other kinds of neurons, and could accumulate dangerous mutations during their many divisions, says Loring. “Not knowing what the cells will become is troubling.”

    But Zhou and the Australian team defend their choices. Russell Kern, chief scientific officer of the International Stem Cell Corporation in Carlsbad, California, which is providing the cells for and managing the Australian trial, says that in preclinical work, 97% of them became dopamine-releasing cells.

    Lorenz Studer, a stem-cell biologist at the Memorial Sloan Kettering Cancer Center in New York City who has spent years characterizing such neurons ahead of his own planned clinical trials, says that “support is not very strong” for the use of precursor cells. “I am somewhat surprised and concerned, as I have not seen any peer-reviewed preclinical data on this approach,” he says.

    Studer’s and Loring’s teams are part of an international consortium that coordinates stem-cell treatments for Parkinson’s. In the next two years, five groups in the consortium plan to run trials using cells fully committed to becoming dopamine-producing cells.

    Regenerative neurobiologist Malin Parmar, who heads one of the teams at Lund University in Sweden, says that the groups “are all rapidly moving towards clinical trials, and this field will be very exciting in the coming years”.

    See the full article here .

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  • richardmitnick 8:56 am on December 29, 2016 Permalink | Reply
    Tags: , , Parkinson’s disease,   

    From U Washington: “Parkinson’s patient dodges, jabs to maintain her mobility” 

    U Washington

    University of Washington

    Barbara Clements

    Boxing is therapy for body and brain alike, leaving woman feeling empowered and less like a victim, she says.

    The Arlington garage, transformed into a gym, greets visitors’ noses and eyes almost simultaneously. A whiff of sweat hangs amid a patchwork of boxing posters covering the walls. In the ring, trainer Bret Summers is putting Suzanne Taitingfong through her paces.

    “Harder, hit me harder,” Summers barks as Taitingfong jabs at the pads Summers holds up as targets. “Okay, now back, back, back, and to the side. Eyes up.”

    Summers moves on to his next trainee while Taitingfong, 60, takes a break and reflects on her journey to this farmland dotted by log cabins, shaggy Highland cattle and dirt roads. She says the hour-long boxing sessions with others who are fighting the effects of Parkinson’s disease is worth the trip.

    “It is easy to feel like a victim with this disease,” she said. “When I walk into the ring, I don’t feel like a victim, I feel empowered. I am physically fighting against the disease.”

    Parkinson’s causes a person’s brain to gradually stop producing a neurotransmitter called dopamine, the loss of which gradually reduces a person’s ability to control movements.

    In 2010, Taitingfong noticed she couldn’t move her shoulder. Balance emerged as a problem. For five years, she was able to moderate symptoms through drugs and exercise, but her body became less her own. The Marysville mother of three felt trapped in her home as her legs torqued painfully with dystonia. On the advice of her daughters, she consulted UW Medicine physicians and decided to try deep brain stimulation to control the spasms and tremors.

    Dr. Andrew Ko, a surgeon, said that drugs such as levodopa can lose their impact over time or begin to have unpleasant side effects. Given that Taitingfong was experiencing both, “she was an excellent candidate for deep brain stimulation,” in which implanted probes and a neurostimulator act as a pacemaker for the brain, controlling and resetting electrical activity in the area of the brain causing the tremors.

    Taitingfong underwent surgery from Ko in January 2016. A follow-up procedure in February programmed the neurostimulator device in her chest, which is hard-wired to her brain. Adjustments began to find just the right amount of electrical activity to control the tremors.

    “Once they found the right combination, my leg immediately relaxed and the tremors subsided,” she said. “My husband said my face lit up and I had the best smile he’d seen in years.”

    She knows it isn’t a cure, but the treatment at UW Medical Center has given her the energy and the time to seek out other activities to keep Parkinson’s advance at bay.

    Her search for activities led her to a gym in Bellevue that promoted boxing for Parkinson’s patients, but the long drive from Marysville led her to seek a closer option. She contacted Summers, a former pro fighter whose uncle also suffers from the disease. Hence the boxing club was created, and it now meets twice a week. Taitingfong hopes to expand club membership and is working with the Marysville YMCA to include classes for Parkinson’s patients.

    “The physical activity makes you feel like a victor,” she said, before returning to spar with Summers. “You don’t quite feel like the victim anymore.”

    See the full article here .

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  • richardmitnick 10:26 am on September 9, 2016 Permalink | Reply
    Tags: , , , Parkinson’s disease,   

    From SA: “Promising Links Found between Different Causes of Parkinson’s” 

    Scientific American

    Scientific American

    September 8, 2016
    Karen Weintraub

    Glitches in cells’ mitochondria power plants underlie various types of cases.

    Mitochondrion, coloured transmission electron micrograph (TEM). Credit: CNRI Getty Images

    Researchers have long believed that problems with mitochondria—the power plants of cells—underlie some cases of Parkinson’s disease. Now a new study details those problems, and suggests that they may form a common thread linking previously unexplained cases of the disease with those caused by different genetic anomalies or toxins.

    Finding a common mechanism behind different suspected causes of Parkinson’s suggests that there might also be a common means to measure, treat or cure it, says Marco Baptista, research director at the nonprofit Michael J. Fox Foundation, a leading center for study and advocacy in the fight against Parkinson’s.

    The study, published Thursday in Cell Stem Cell, did identify a possible way to reverse the damage of Parkinson’s—but only in individual cells and fruit flies. Finding a treatment that does the same thing in people will be challenging, Baptista says.

    Roughly one million Americans have Parkinson’s disease, which is characterized by motor problems and can cause other symptoms including cognitive and gastrointestinal difficulties. About 1 to 2 percent of cases are linked to mutations in the LRRK2 gene, with far fewer associated with genes known as PINK1 and Parkin. Exposure to environmental factors such as toxic chemicals can also lead to Parkinson’s, although most cases have no obvious cause.

    In the new paper Xinnan Wang, an assistant professor of neurosurgery at Stanford University, and her colleagues show that mitochondria are underpowered in several types of Parkinson’s and that these mitochondria also release toxic chemicals. Looking at fly models of the disease as well as cells taken from patients, the researchers found that they could correct these problems and reverse neurodegeneration if they reduced levels of a protein involved in mitochondrial activity. “I think it’s a really cool piece of work,” says Thomas Schwarz, a professor of neurology and neurobiology at Harvard University who was not involved in the research but was Wang’s postdoctoral adviser.

    It had been clear that Parkinson’s cases caused by toxins, or by Parkin or PINK1 mutations, involved mitochondria problems, Schwarz says. But the new paper shows that Parkinson’s driven by the LRRK2 gene is also subject to the same mechanism and hints that unexplained cases may also involve the same difficulties in clearing faulty mitochondria from cells. “Here’s the best evidence yet that even those forms are some sort of mitochondriopathy,” Schwarz says. “Seeing those completely disparate, unrelated spontaneous cases—linked up to this question of how are mitochondria cleared and how is their movement controlled—is absolutely fascinating.”

    One question that remains is why would a general problem of cellular physiology cause Parkinson’s? Both Schwarz and Wang have hypotheses: Wang says that the brain cells whose degeneration leads to Parkinson’s—the cells that control release of the neurotransmitter dopamine—are particularly energy-dependent and vulnerable to stress. Deprive a skin cell of energy and it won’t work as efficiently; deprive a dopaminergic neuron of energy and it may die, she adds.

    Schwarz says these neurons are also distinctive in their anatomy. They have so many branches linking them to other brain cells that they can extend up to 4.5 meters in length. Mitochondria are distributed along these branches and must continually be refreshed, with old ones cleared out on the order of some 33,000 mitochondria per cell each day. “That’s just a staggering burden for the cell to carry,” says Schwarz, who in his own research explores how mitochondria move along these axons. “That’s why even a minor slowing or defect in the way the mitochondria are cleared out, or damaged proteins are dealt with, winds up being a major crisis for a cell that has 4.5 meters of axon, compared to a liver cell or even your average neuron elsewhere in the brain.” Figuring out a way to measure this overload before it brings about symptoms of Parkinson’s might lead to earlier diagnoses, before irrevocable damage is done, he adds.

    The paper released Thursday addresses the mystery of how Parkinson’s caused by PINK1 and Parkin mutations, which are known to affect mitochondria, could share the same symptoms as those caused by mutations in the LRRK2 gene, which is involved in how cells take out their trash. Wang and her team found that problems turn up when spent mitochondria are not cleared properly from the cell, a situation that provides a link between the two problems. The different mutations may act on the mitochondria differently but both end up causing the same mitochondrial dysfunction, Wang says. These dysfunctional mitochondria also produce toxins, much like a power plant does, she says, further damaging the cells.

    Asa Abeliovich, a pathologist and neurologist at Columbia University who was not part of this study, says the paper effectively links these two genetic routes to Parkinson’s: the garbage disposal problem and the toxic accumulation that occurs when cellular energy plants go awry. Abeliovich, however, thinks it is still speculative to conclude these problems are also to blame for the noninherited cases of Parkinson’s.

    Wang agrees that she needs to test her theories in other models of Parkinson’s before declaring that a cure might lie in fixing mitochondrial problems. Just because the team found the mitochondrial problems in human cells and in a fly model of Parkinson’s “doesn’t necessarily mean that in humans it is the cause [of Parkinson’s],” Wang says, “but suggests it is a possibility—[and] suggests a future direction to look in human patients and see if lowering this protein has any therapeutic benefits.”

    See the full article here .

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  • richardmitnick 6:49 am on August 30, 2016 Permalink | Reply
    Tags: , , Parkinson’s disease,   

    From U Cambridge: “Tiny changes in Parkinson’s protein can have “dramatic” impact on processes that lead to the disease” 

    U Cambridge bloc

    Cambridge University

    30 Aug 2016
    Tom Kirk

    Image of “amyloid fibrils”; thread-like structures which form after the protein alpha-synuclein aggregates. Plaques (protein deposits) consisting of this protein have been found in the brains of Parkinson ’s Disease patients and linked to disease. Credit: Patrick Flagmeier

    In a new study, a team of academics at the Centre for Misfolding Diseases, in the Department of Chemistry at the University of Cambridge, show that tiny changes in the amino acid sequence of the protein alpha-synuclein can have a dramatic effect on microscopic processes leading to its aggregation that may occur in the brain, eventually resulting in someone being diagnosed with Parkinson’s Disease.

    Alpha-synuclein is a protein made up of 140 amino acids, and under normal circumstances plays an important part in helping with the smooth flow of chemical signals in the brain.

    Parkinson’s Disease is thought to arise because, for reasons researchers still do not fully understand, the same protein sometimes malfunctions. Instead of adopting the specific structural form needed to do its job, it misfolds and begins to cluster, creating toxic, thread-like structures known as amyloid fibrils. In the case of Parkinson’s Disease, these protein deposits are referred to as Lewy-bodies.

    The new study examined mutated forms of alpha-synuclein which have been found in people from families with a history of Parkinson’s Disease. In all cases, these mutations involved just one change to the protein’s amino acid sequence.

    Although the differences in the sequence are small, the researchers found that they can have a profound effect on how quickly or slowly fibrils start to form. They also found that the mutations strongly influence a process called “secondary nucleation”, in which new fibrils are formed, in an auto-catalytic manner, at the surface of existing ones and thus enable the disease to spread.

    The study stresses that these findings do not explain why humans get the disease. Parkinson’s Disease does not always emerge as a result of the mutations and has multiple, complex causes, which are not fully understood.

    Patrick Flagmeier, a PhD student at St John’s College, University of Cambridge, and the study’s lead author, said: “As a finding, it helps us to understand fundamental things about the system by which this disease emerges. In the end, if we can understand all of this better, that can help us to develop therapeutic strategies to confront it. Our hope is that this study will contribute to the global effort towards comprehending why people with these mutations get the disease more frequently, or at a younger age.”

    Although people who do not have mutated forms of alpha-synuclein can still develop Parkinson’s Disease, the five mutations studied by the research team were already known as “familial” variants – meaning that they recur in families where the disease has emerged, and seem to increase the likelihood of its onset.

    What was not clear, until now, is why they have this effect. “We wanted to know how these specific changes in the protein’s sequence influence its behaviour as it aggregates into fibrils,” Flagmeier said.

    To understand this, the researchers conducted lab tests in which they added each of the five mutated forms of alpha-synuclein, as well as a standard version of the protein, to samples simulating the initiation of fibril formation, their growth and their proliferation.

    The first round of tests examined the initiation of aggregation, using artificial samples recreating conditions in which misfolded alpha-synuclein attaches itself to small structures that are present inside brain cells called lipid vesicles, and then begins to cluster.

    The researchers then tested how the different versions of the protein influence the ability of pre-formed fibrils to extend and grow. Finally, they tested the impact of mutated proteins on secondary nucleation, in which, under specific conditions, the fibrils can multiply and start to spread.

    Overall, the tests revealed that while the mutated forms of alpha-synuclein do not notably influence the fibril growth, they do have a dramatic effect on both the initial formation of the fibrils, and their secondary nucleation. Some of the mutated forms of the protein made these processes considerably faster, while others made it almost “undetectably slow”, according to the researchers’ report.

    “We have only recently discovered the autocatalytic amplification process of alpha-synuclein fibrils, and the results of the present study will help us to understand in much more detail the mechanism behind this process, and in what ways it differs from the initial formation of aggregates.” said Dr. Alexander Buell, one of the senior authors on the study.

    Why the mutations have this impact remains unclear, but the study opens the door to understanding this in detail by identifying, for the first time, that they have such a dramatic impact on very particular stages of the process.

    Dr. Céline Galvagnion, another of the senior authors on the study, said: “This study quantitatively correlates individual changes in the amino acid sequence of alpha-synuclein with its tendency to aggregate. However, the effect of these mutations on other parameters such as the loss of the protein’s function and the efficiency of clearance of alpha-synuclein needs to be taken into account to fully understand the link between the familial mutations of alpha-synuclein and the onset of Parkinson’s Disease.”

    “The effects we observed were changes of several orders of magnitude and it was unexpected to observe such dramatic effects from single-point mutations,” Flagmeier said. “It seems that these single-point mutations in the sequence of alpha-synuclein play an important role in influencing particular microscopic steps in the aggregation process that may lead to Parkinson’s Disease.”

    The full study, which also involves Professors Chris Dobson and Tuomas Knowles, is published in the journal, Proceedings of the National Academy of Sciences.


    Flagmeier, P. et. al: Mutations associated with familial Parkinson’s disease alter the initiation and amplification steps of α-synuclein aggregation. PNAS (2016): DOI: 10.1073/pnas.1604645113

    See the full article here .

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