Scientists track sequence of events necessary for apoptosis to occur properly

December 20, 2016

Schematic model depicting the role of IRBIT-Bcl2l10 interplay in physiological and stress conditions. In physiological condition, in WT cells, IRBIT promotes ER-mitochondria contact rendering Ca2+ transfer easier between the two organelles. The additive effect of Bcl2l10 and phosphorylated IRBIT on IP3R maintains Ca2+ transfer to a low level. In IRBIT KO cells, although Ca2+ released through IP3R is increased due to absence of IRBIT, Ca2+ transfer to the mitochondria is reduced because of the great reduction of ER-mitochondria contact. Following an apoptotic stimuli, Ca2+ release from the ER is increased. In WT cells, IRBIT dephosphorylation induces its translocation together with Bcl2l10 allowing a massive Ca2+ transfer from ER to mitochondria. On contrary, in IRBIT KO cells, Bcl2l10 is no longer displaced from MAMs what reduces Ca2+ release from ER. This, combined to the reduction of ER-mitochondria contact, prevents massive Ca2+ transfer to mitochondria and then greatly attenuates apoptosis. Credit: RIKEN

Billions of cells in our bodies die every day in an important process called apoptosis. Now, researchers at the RIKEN Brain Science Institute have mapped out a sequence of events that are necessary for apoptosis to occur properly. Published in eLife, the study focuses on the protein IRBIT and how its action near mitochondria in our cells can set off a chain reaction that leads to programmed cell death.

Disruptions in proper apoptosis can lead to serious medical consequences. As team leader Katsuhiko Mikoshiba explains, "Excessive apoptosis in the brain is associated with several neurodegenerative diseases, while impaired apoptosis is related to some cancers and tumor formation."

Events that happen inside our cells are often controlled by interactions between proteins and modifications of proteins that change how they can interact with each other. Mikoshiba and his team have already shown that apoptosis in neurons can be initiated when certain proteins binds to IP3 receptors. In their new study, the team investigated IRBIT, another protein commonly found in the brain that can bind to the IP3 receptor.

In a series of studies, the researchers showed that the presence of IRBIT promoted normal apoptosis. "We were actually quite surprised," notes first author Benjamin Bonneau. "We initially expected that IRBIT would function to suppress cell death."

The reason for this prediction was that IRBIT has been primarily described as a protein that reduces cellular calcium levels, a phenomenon that can lead to cell death. Additionally, IRBIT is located in the same parts of the body—including the developing nervous system—as Bcl2l10, another protein that is known to reduce apoptosis and which also binds to the same region of the IP3 receptor as IRBIT. The key factor in this process is the flow of calcium ions between two organelles within a cell—the ER and mitochondria. When Bcl2l10 is attached to the IP3 receptor located in the ER membrane, it reduces the flow of calcium into the mitochondria, which prevents apoptosis.

In their new study, the team first showed that IRBIT and Bcl2l10 naturally attach to different places on the IP3 receptor, and that they attach to each other. This is why they initially thought that they work together to prevent apoptosis. However, further testing revealed an important event that always preceded apoptosis—IRBIT loses a phosphate group. Protein function is often altered through small additions or subtractions. The team showed that in this case, the loss of the phosphate group prevents IRBIT from staying attached to the IP3 receptor. Instead it moves away from the ER, and drags Bcl2l10 with it. When this happens, the team saw that without Bcl2l10, calcium flow into the mitochondria increased, which led to cell death.

Understanding IRBIT's role in facilitating apoptosis has implications for treating cancer that is associated with low levels of IRBIT expression. Bonneau notes that, "Because reduced IRBIT expression may contribute to tumor formation, the next step is to determine to what extent modulating IRBIT expression contributes to cancer formation, and if this is the case, what organs are the most sensitive.

Mikoshiba adds, "Neurodegenerative diseases such as Huntington's disease and Parkinson's disease are characterized by excessive apoptosis. Knowing IRBIT's involvement gives us a new target for investigation. As IRBIT is highly expressed in the brain, the chances are good that we will be able to find a connection, which could lead to new treatment possibilities."

More information: "IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact", eLife, DOI: 10.7554/eLife19896 

Journal reference: eLife

Provided by: RIKEN

http://medicalxpress.com/news/2016-12-scientists-track-sequence-events-apoptosis.html

Ask the Pharmacist: Here’s how you help both Parkinson’s and diabetes

December 19, 2016 - Suzy Cohen, Columnist

When you think of Parkinson’s disease, you probably think of it as a progressive disorder affecting movement and causing tremors of the hands, arms, legs, jaw and elsewhere. The condition causes movements to be slowed, and a sensation of rigidity and stiffness of the limbs and trunk. Balance can be impacted, too. A related condition of Lewy Body Disease may look very similar to Parkinson’s, but doesn’t have to show up with tremors. The cognitive fluctuations are hallmark to both disorders.

The one thing they have in common is the issue with dopamine. There’s some kind of malfunction associated with either the production of dopamine or the transport of this ‘passion hormone’ across the synapse… or maybe suppressed ‘receptor sensitivity,’ meaning the dopamine is there but it doesn’t get hugged into the cell. This is known as post-synaptic D2 receptor down-regulation. It can happen to people who do not have Parkinson’s, for example, those afflicted by withdrawal symptoms from hydrocodone, or kids who took methylphenidate. When SPECHT studies were conducted in children on ADHD stimulants, researchers concluded that their D2 (dopamine) receptors were destroyed. They had a maximum of 20 percent functional ability, and this was published in Neuropediatrics in 2003.

I want to keep my article simple today because what I have to tell you is rather exciting! It’s about a diabetes drug that’s in Phase 2 studies (MSDC-0160, it’s not named yet.) The emerging research suggests its role in Parkinson’s could be even more profound. It’s not due to balancing blood sugar, either; it’s because this diabetes agent improves mitochondrial function. Your mitochondria are the organelles that produce energy for you. They help you make ATP. So this diabetes drug belongs to the category of “Mitochondrial Target of Thiazolidinediones” modulators or mTOT for short. The mTOT drugs make your body more sensitive to insulin. They are insulin sensitizers.

Forget insulin for a minute! The novelty of mTOT drugs is really about energy. If you can improve mitochondrial function in brain cells, you then restore the cells' ability to convert basic nutrients into energy. Consequently, the cells' ability to handle potentially harmful proteins is normalized, which leads to reduced inflammation and reduced death and dysfunction of the neurons. This may help Alzheimer’s, Parkinson’s disease, Lewy body dementia and other types of cognitive decline. When I worked in Florida nursing homes for seven years, we saw a lot of this and we had very few tools to use. We had levodopa, a drug from the 70’s that’s still used today, but ramping up dopamine isn’t the cure. Side effects are disturbing.

If this topic is of interest, I have written a more comprehensive version and I’ll email it to you when you sign up for my free newsletter at my website, suzycohen.com. Before I leave you, one more thing; your gut microbiome matters, so consider high-quality probiotics. There is a direct connection between the microbiome and Parkinson’s and other neurological disorders including Autism.

Suzy Cohen is a registered pharmacist. The information presented here is not intended to treat, cure or diagnose any condition. Visit SuzyCohen.com.

http://www.naplesnews.com/story/news/local/communities/marco-eagle/2016/12/19/ask-pharmacist-heres-how-you-help-both-parkinsons-and-diabetes/95515538/

New Biomarker Predicts Alzheimer’s and Link to Diabetes

NEUROSCIENCE NEWSDECEMBER 19, 2016

Summary: Autotaxin predicts type 2 diabetes and cognitive decline, a new study reports.

Source: Iowa State University.

Willette’s previous research found a strong association between insulin resistance and memory decline and detrimental brain outcomes, increasing the risk for Alzheimer’s disease. NeuroscienceNews.com image is for illustrative purposes only.

An enzyme found in the fluid around the brain and spine is giving researchers a snapshot of what happens inside the minds of Alzheimer’s patients and how that relates to cognitive decline.

Iowa State University researchers say higher levels of the enzyme, autotaxin, significantly predict memory impairment and Type 2 diabetes. Just a one-point difference in autotaxin levels – for example, going from a level of two to a three – is equal to a 3.5 to 5 times increase in the odds of being diagnosed with some form of memory loss, said Auriel Willette, an assistant professor of food science and human nutrition at Iowa State.

Autotaxin, often studied in cancer research, is an even stronger indicator of Type 2 diabetes. A single point increase reflects a 300 percent greater likelihood of having the disease or pre-diabetes. The results are published in the Journal of Alzheimer’s Disease. Willette and Kelsey McLimans, a graduate research assistant, say the discovery is important because of autotaxin’s proximity to the brain.

“We’ve been looking for metabolic biomarkers which are closer to the brain. We’re also looking for markers that reliably scale up with the disease and have consistently higher levels across the Alzheimer’s spectrum,” Willette said. “This is as directly inside of the brain as we can get without taking a tissue biopsy.”

Willette’s previous research found a strong association between insulin resistance and memory decline and detrimental brain outcomes, increasing the risk for Alzheimer’s disease. Insulin resistance is a good indicator, but Willette says it has limitations because what happens in the body does not consistently translate to what happens in the brain. That is why the correlation with this new enzyme found in the cerebrospinal fluid is so important.

“It has a higher predictive rate for having Alzheimer’s disease,” McLimans said. “We also found correlations with worse memory function, brain volume loss and the brain using less blood sugar, which have also been shown with insulin resistance, but autotaxin has a higher predictive value.”

Physical health linked to memory

The fact that autotaxin is a strong predictor of Type 2 diabetes and memory decline emphasizes the importance of good physical health. Researchers say people with higher levels of autotaxin are more likely to be obese, which often causes an increase in insulin resistance.

Willette says autotaxin levels can determine the amount of energy the brain is using in areas affected by Alzheimer’s disease. People with higher autotaxin levels had fewer and smaller brain cells in the frontal and temporal lobes, areas of the brain associated with memory and executive function. As a result, they had lower scores for memory and tests related to reasoning and multitasking.

“Autotaxin is related to less real estate in the brain, and smaller brain regions in Alzheimer’s disease mean they are less able to carry out their functions,” Willette said. “It’s the same thing with blood sugar. If the brain is using less blood sugar, neurons have less fuel and start making mistakes and in general do not process information as quickly.”

Researchers analyzed data from 287 adults collected through the Alzheimer’s Disease Neuroimaging Initiative, a public-private partnership working to determine whether MRI and PET scans as well as biological markers can measure the progression of cognitive impairment and Alzheimer’s disease. The data came from adults ranging in age from 56 to 89 years old. Study participants completed various tests to measure cognitive function. This included repeating a list of words over various time increments.

ABOUT THIS ALZHEIMER’S DISEASE RESEARCH ARTICLE

Funding: The research was supported by an Iowa State Presidential Initiative for Interdisciplinary Research grant and a National Institutes of Health grant.

Source: Auriel Willette – Iowa State University 
Image Source: NeuroscienceNews.com image is in the public domain.

Original Research: Abstract for “Autotaxin is Related to Metabolic Dysfunction and Predicts Alzheimer’s Disease Outcomes” by McLimans, Kelsey E. and Willette, Auriel A. in Journal of Alzheimer’s Disease. Published online December 2016 doi:10.3233/JAD-160891

Abstract

Autotaxin is Related to Metabolic Dysfunction and Predicts Alzheimer’s Disease Outcomes

Background: Obesity and insulin resistance are associated with neuropathology and cognitive decline in Alzheimer’s disease (AD).

Objective: Ecto-nucleotide pyrophosphatase/phosphodiesterase 2, also called autotaxin, is produced by beige adipose tissue, regulates metabolism, and is higher in AD prefrontal cortex (PFC). Autotaxin may be a novel biomarker of dysmetabolism and AD. Methods: We studied Alzheimer’s Disease Neuroimaging Initiative participants who were cognitively normal (CN; n = 86) or had mild cognitive impairment (MCI; n = 135) or AD (n = 66). Statistical analyses were conducted using SPSS software. Multinomial regression analyses tested if higher autotaxin was associated with higher relative risk for MCI or AD diagnosis, compared to the CN group. Linear mixed model analyses were used to regress autotaxin against MRI, FDG-PET, and cognitive outcomes. Spearman correlations were used to associate autotaxin and CSF biomarkers due to non-normality. FreeSurfer 4.3 derived mean cortical thickness in medial temporal lobe and prefrontal regions of interest. 

Results: Autotaxin levels were significantly higher in MCI and AD. Each point increase in log-based autotaxin corresponded to a 3.5 to 5 times higher likelihood of having MCI and AD, respectively. Higher autotaxin in AD predicted hypometabolism in the medial temporal lobe [R2 = 0.343, p < 0.001] and PFC [R2 = 0.294, p < 0.001], and worse performance on executive function and memory factors. Autotaxin was associated with less cortical thickness in PFC areas like orbitofrontal cortex [R2 = 0.272, p < 0.001], as well as levels of total tau, p-tau181, and total tau/Aβ1–42. 

Conclusions: These results are comparable to previous reports using insulin resistance. CSF autotaxin may be a useful dysmetabolism biomarker for examining AD outcomes and risk.

“Autotaxin is Related to Metabolic Dysfunction and Predicts Alzheimer’s Disease Outcomes” by McLimans, Kelsey E. and Willette, Auriel A. in Journal of Alzheimer’s Disease. Published online December 2016 doi:10.3233/JAD-160891

http://neurosciencenews.com/alzheimers-diabetes-5779/

ALZHEIMER’S ADVANCE – NEW DRUG RESTORES MEMORY AND PROLONGS LIFE: MOUSE STUDY

NEUROSCIENCE NEWSDECEMBER 19, 2016

Summary: Researchers have identified a possible new drug target that could help to restore memory loss and improve longevity in Alzheimer’s disease.

Source: University of Leicester.

Picture of nerve cells dying in the brain of prion-diseased mice. The nerves are stained pink and can be seen dying in the CA1 region of the hippocampus. NeuroscienceNews.com image is credited to University of Leicester.

Breakthrough findings demonstrate a possible target and potential drug treatment to restore memory loss and extend life span in mice with neurodegeneration.

“We have treated mice with a new type of drug, and found that these drugs can not only improve symptoms of brain degeneration, such as cognitive decline, but can also extend the life-span of these terminally-sick mice. Our study opens up avenues for researchers to look at new drugs that treat the symptoms of Alzheimer’s and also slow disease progression” said Professor Andrew Tobin.

An international team of scientists has announced a new advance in the fight against Alzheimer’s disease by identifying a new drug target for not only improving symptoms of brain degeneration – but also to extend the life-span of the terminally ill mice.

The four-year study by Medical Research Council (MRC) scientists based at the MRC Toxicology Unit at the University of Leicester is published in the Journal of Clinical Investigation. The study was led by Professor Andrew Tobin alongside colleagues from pharmaceutical company Eli Lilly and Company and the Monash Institute for Pharmaceutical Sciences in Australia. The project was also partly supported by the Wellcome Trust.

Corresponding author Professor Tobin, who alongside the lead researcher Dr Sophie Bradley has since moved from the University of Leicester to the University of Glasgow, said: “The paper describes drug-like molecules that can restore memory loss and slow progression of prion neurodegenerative disease in a manner that relates to the potential of these drugs in human Alzheimer’s disease.

“We have been using mice whose brain cells are progressively dying, similar to what happens in Alzheimer’s disease. This project focuses on a particular protein in the brain, which is proposed to be involved in Alzheimer’s disease, and as such could be a potential target for new drugs.

“We have treated mice with a new class of drug, and found that these drugs can not only improve symptoms of brain degeneration, such as cognitive decline, but can also extend the life-span of these terminally-sick mice.”

The researchers state that drugs which activate this protein receptor in the brain have previously been tested in clinical trials for Alzheimer’s disease, and showed positive results with respect to improving cognition, but the patients experienced a large number of adverse side effects. This new class of drug is more selective and does not cause any side-effects when administered to mice in the study.

The study authors believe that this offers hope in the design of new drugs for improving cognition and extending life span.

Professor Tobin said: “This work may provide important information as to whether this protein is a viable drug target in the treatment of diseases associated with the progressive death of brain cells. This is of great importance to society, based on the fact that the treatment options for Alzheimer’s disease are very limited – there are no cures for Alzheimer’s disease and current treatments are focused on relieving some of the symptoms.

“What we have found is a novel class of drugs, called allosteric ligands, that target a protein called the M1 muscarinic receptor, which is present in the brain. Activating this receptor protein can not only improve cognitive function in mice with progressive brain degeneration, but when administered daily, can extend life span.”

The scientists say the work is important because it focuses on identifying a treatment that not only improves symptoms associated with neurodegeneration, like current treatments, but also identifies a new strategy for slowing disease progression and extending life-span.

Professor Tobin said: “Alzheimer’s disease is the most common form of dementia, and it affects an estimated 850,000 people in the UK alone. There are no treatments that can slow or halt the progression of Alzheimer’s, and patients are treated with drugs which temporarily mask the symptoms of the disease. Often these treatments are associated with side-effects which can limit patient compliance.

“I am proud to be involved in a collaboration with researchers across the world to address one of the world’s major healthcare challenges. Our study opens up avenues for researchers to look at new drugs that treat the symptoms of Alzheimer’s and also slow disease progression.”

ABOUT THIS ALZHEIMER’S DISEASE RESEARCH ARTICLE

Funding: The research was funded by Medical Research Council, Wellcome Trust.

Source: Andrew Tobin – University of Leicester 

Image Source: NeuroscienceNews.com image is credited to University of Leicester.

Original Research: Full open access research for “M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss” by Sophie J. Bradley, Julie-Myrtille Bourgognon, Helen E. Sanger, Nicholas Verity, Adrian J. Mogg, David J. White, Adrian J. Butcher, Julie A. Moreno, Colin Molloy, Timothy Macedo-Hatch, Jennifer M. Edwards, Jurgen Wess, Robert Pawlak, David J. Read, Patrick M. Sexton, Lisa M. Broad, Joern R. Steinert, Giovanna R. Mallucci, Arthur Christopoulos, Christian C. Felder, and Andrew B. Tobin in Journal of Clinical Investigation. Published online December 19 2016 doi:10.1172/JCI87526

Abstract

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss

The current frontline symptomatic treatment for Alzheimer’s disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR–selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.

“M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss” by Sophie J. Bradley, Julie-Myrtille Bourgognon, Helen E. Sanger, Nicholas Verity, Adrian J. Mogg, David J. White, Adrian J. Butcher, Julie A. Moreno, Colin Molloy, Timothy Macedo-Hatch, Jennifer M. Edwards, Jurgen Wess, Robert Pawlak, David J. Read, Patrick M. Sexton, Lisa M. Broad, Joern R. Steinert, Giovanna R. Mallucci, Arthur Christopoulos, Christian C. Felder, and Andrew B. Tobin in Journal of Clinical Investigation. Published online December 19 2016 doi:10.1172/JCI87526

http://neurosciencenews.com/memory-alzheimers-drug-longevity-5780/

Couple donates $75 million for research and patient care at two top Texas health institutions

December 19, 2016

A $25 million grant to MD Anderson Cancer Center will fund melanoma and prostate cancer research and patient care. Photo courtesy of MD Anderson

Healthcare and medical research in Texas just got a major boost. The Mulva Family Foundation announced a $75 million donation to the University of Texas at Austin and the University of Texas MD Anderson Cancer Center in Houston.

A $50 million gift was given to advance neuroscience, with an initial focus on Alzheimer’s disease, Parkinson’s disease, stroke, and bipolar disorder. The grant will create the Mulva Clinic for the Neurosciences at the new Dell Medical School in Austin. 

"We are pleased to establish a new and innovative neurology clinic combining UT Austin’s state-of-the-art research with advanced clinical operations for these widespread and difficult diseases that impact so many people and families,” said Jim and Miriam Mulva in a release.

The two are long-time supporters of advancing healthcare in Texas. Past donations by the Mulva family to the university include multi-year pledges of $40 million to support the McCombs School of Business and $20 million to support the Cockrell School of Engineering.

In addition to creating the Mulva Clinic for the Neurosciences, the Mulva Family Foundation has given $25 million to fund melanoma and prostate cancer research and patient care at MD Anderson Cancer Center in Houston. The goal of the gift, which will be divided equally between prostate and melanoma research, is to advance research and patient care towards two of the most aggressive types of cancer.

“We are profoundly grateful for the Mulva Family Foundation’s remarkable support of MD Anderson’s mission,” said MD Anderson president Ronald A. DePinho, in the release. “Together, we will change the statistics and create new hope for patients and their loved ones facing the challenges of cancer.”

James Mulva is past chairman and CEO of ConocoPhillips and is chair of the MD Anderson Cancer Center Board of Visitors. The couple split their time between Austin and Green Bay, Wisconsin.

http://houston.culturemap.com/news/innovation/12-19-16-couple-donates-75-million-for-research-and-patient-care-at-two-top-texas-health-institutions/

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Team discovers powerful defenders of the brain—with big implications for disease

December 19, 2016

The immune cells play a vital role in response to injuries to the spinal cord, University of Virginia School of Medicine researchers have determined. Credit: Sachin Gadani | University of Virginia School of Medicine

A rare and powerful type of immune cell has been discovered in the meninges around the brain, suggesting the cells may play a critical but previously unappreciated role in battling Alzheimer's, multiple sclerosis, meningitis and other neurological diseases, in addition to supporting our healthy mental functioning. By harnessing the cells' power, doctors may be able to develop new treatments for neurological diseases, traumatic brain injury and spinal cord injuries - even migraines.

Further, University of Virginia School of Medicine researchers suspect the cellsmay be the missing link connecting the brain and the microbiota in our guts, a relationship already shown important in the development of Parkinson's disease.

Unexpected Presence

The cells, known as "type 2 innate lymphocytes," previously have been found in the gut, lung and skin - the body's barriers to disease. Their discovery in the meninges, the membranes surrounding the brain, comes as a surprise. They were found as UVA researcher Jonathan Kipnis, PhD, explored the implications of his lab's game-changing discovery last year that the brain and the immune system are directly connected via vessels long thought not to exist

"This all comes down to immune system and brain interaction," said Kipnis, chairman of UVA's Department of Neuroscience. "The two were believed to be completely not communicating, but now we're slowly, slowly filling in this puzzle. Not only are these [immune] cells present in the areas near the brain, they are integral to its function. When the brain is injured, when the spinal cord is injured, without them, the recovery is much, much worse."

A composite image showing the immune cells. In addition to being important defenders of the brain, the cells may also may be the missing link connecting the brain's immune response to the microbiome in the gut. That relationship already has been shown important in Parkinson's disease. Credit: Sachin Gadani / University of Virginia School of Medicine

Curiously, the immune cells were found along the vessels discovered by Kipnis' team. "They're right on the lymphatics, which is really weird," noted researcher Sachin Gadani. "You have the lymphatics and they're stacked right on top. They're not inside of them - they're around them."

Important Immune Role

The immune cells play several important roles within the body, including guarding against pathogens and triggering allergic reactions. In exploring their role in protecting the brain, the Kipnis team has determined they are vital in the body's response to spinal cord injuries. But it's their role in the gut that makes Kipnis suspect they may be serving as a vital communicator between the brain's immune response and our microbiomes. That could be of great importance, because our intestinal flora is critical for maintaining our health and wellbeing.

"These cells are potentially the mediator between the gut and the brain. They are the main responder to microbiota changes in the gut. They may go from the gut to the brain, or they may just produce something that will impact those cells. But you see them in the gut and now you see them also in the brain," Kipnis said. "We know the brain responds to things happening in the gut. Is it logical that these will be the cells that connect the two? Potentially. We don't know that, but it very well could be."

While much more research needs to be done to understand the role of these cells in the meninges, Gadani noted that it's almost certain that the cells are important in a variety of neurological conditions. "It would be inconceivable they're not playing a role in migraines and certain conditions like that," he said. "The long-term goal of this would be developing drugs for targeting these cells. I think it could be highly efficacious in migraine, multiple sclerosis and possibly other conditions."

The findings have been published online by the Journal of Experimental Medicine.

More information: Journal of Experimental Medicine, DOI: 10.1084/jem.20161982 

Journal reference: Journal of Experimental Medicine

Provided by: University of Virginia

http://medicalxpress.com/news/2016-12-team-powerful-defenders-brainwith-big.html

New medicine: How the gut breaks the mind

 GOVIND VIJAYKUMAR

 

December 18, 2016

Parkinson’s disease has for the first time been linked to bacteria in your stomach.

The discovery of the brain-gut bacteria link can lead to the development of next-generation probiotics which can not just cure, but even one day prevent Parkinson’s disease in humans.

Parkinson’s disease was first discovered in 1817. British pharmacist James Parkinson wrote Shaking Palsy, an essay documenting a total of six cases marked by tremors, loss of posture and muscle strength. But there were clues to this sinister disease much before Mr Parkinson even set out to print his findings. The Egyptians wrote about a “drooling king” and even the Bible has a reference to tremors. Which makes Parkinson’s disease, one of the oldest, unsolved mysteries still haunting the human body.

But a new study by experts at the Californian Institute of Technology claims the key to understanding this degeneration of the brain, lies in the stomach. More specifically, they have formally linked Parkinson’s to abnormalities in the gut.

For years, constipation has been the first clue. Researchers noticed that people suffering from Parkinson’s had reported constipation at least 10 years before the onset of characteristic tremors. These studies went on to suggest that causes and symptoms of PD were not limited to the human head.

But the Caltech research has for the first time proven the existence gut-brain link. And they used mice.

Lead researcher Sarkis Mazmanian and his team showed how tweaking with gut bacteria allowed them to “trigger” the disease in the mice. Much of this three-part study revolves around a protein called alpha-synuclein. The cells in a human brain die off due to an accumulation of this protein — which is when PD sets in.

The mice used in the study were genetically modified to over-produce alpha-synuclein and the only difference between the two sets of rodents was this — one set had no gut bacteria and the other had a full environment in their intestines. The mice lacking bacteria were functioning normally until they were injected with certain chemicals that are commonly manufactured by gut bacteria. The test was to determine if even the germ-free mice would show symptoms if gut bacteria activity was triggered in them. And they did.

In the third test, they injected samples of gut bacteria from human patients of Parkinson’s into the germ-free mice. And soon, the mice started exhibiting symptoms of the disease, proving that anomalies in the gut were directly responsible for brain damage.

“What this tells you is that it is not the presence or absence of bacteria that matters, it is the types of bacteria that are there," Mazmanian was quoted as saying.

The discovery is the first big step towards tracing the origins of Parkinson’s disease. The results can lead to development of next-generation probiotics which can not just cure, but prevent the disease in humans. Because we now know that chemicals in the gut can be the direct triggers of neurological breakdowns.

“This was the ‘eureka’ moment, the mice were genetically identical, the only difference was the presence or absence of gut microbiota. Now we were quite confident that gut bacteria regulate, and are even required for, the symptoms of Parkinson’s disease,” Timothy Sampson, who was part of the team, said. The experiment is game-changing because we finally have new targets in the fight against Parkinson’s. And the gut-brain link widens the brief for the development of new drugs. We don’t have to aim for just the head, anymore.

http://www.asianage.com/life/health/181216/new-medicine-how-the-gut-breaks-the-mind.html

Determining the Relationship Between Protein Function and Amyloid Toxicity

December 18, 2016

Amyloids are protein fragments that can accumulate and lead to diseases such as Alzheimer’s and Parkinson’s. Researchers found that a protein generally not associated with amyloid disease could be induced to form fragments by specific self-derived peptides.

 The build-up of protein fragments called amyloids contributes to a number of human diseases, including Alzheimer’s, Parkinson’s and type II diabetes. In healthy humans, amyloids generally have lost their protein function and are broken down. In cases of disease however, amyloids aggregate and form clumps, or fibrils, that can disrupt the healthy function of nearby structures and organs. It remains to be seen what exactly determines amyloid toxicity, or the tendency of amyloids to aggregate rather than be eliminated from the body.

In a new study published in Science, Gallardo et al. investigated if a protein with known amyloidogenic potential, which does not aggregate normally, could be induced to with an amyloidogenic fragment of itself. The rationale behind this is that studies have shown that this potential in vitro and in vivo aggregation is more pronounced within similar peptides. The vascular endothelial growth factor receptor 2 (VEGFR2) was used because we have good knowledge of the peptide, and a synthetic peptide termed “vascin” was used that consists of a repeated amyloidogenic sequence from VEGFR2. The vascin peptide was tested in mice models in environments with VEGFR2 and without.

The results of the study show that amyloid toxicity is dependent on its biological context. Vascin did not display amyloid toxicity in cells not expressing VEGFR2 or cells not dependent on VEGFR2 function, but in VEGFR2-dependent cells, vascin was toxic and resulted in a loss of function for the cell. This displays that amyloid toxicity is not an inherent trait of amyloids, but rather a function of their biological environment. The findings also show that an amyloidogenic protein that does not normally express amyloid toxicity can be induced to aggregate with specific peptide fragments. This is significant because researchers estimate that most proteins have amyloidogenic regions, but few of them display amyloid toxicity in normal conditions, indicating most proteins can be induced into aggregation.

The research group of Gallardo et al. demonstrate how amyloid toxicity is highly dependent on the biological environment of the cell. In this case, cells had to be dependent on VEGFR2 function for vascin to have toxic function. The ability to induce aggregation in a normally nontoxic peptide indicates that most proteins can be induced to aggregate given the right peptide fragment and biological circumstances. Future studies should focus on clarifying what specific aspects of amyloids lend themselves to aggregation.

Written By: Wesley Tin, BMSc

http://www.medicalnewsbulletin.com/determining-relationship-protein-function-amyloid-toxicity/

Iran builds brain stimulator tDCS device

News ID: 3852825 - Sun 18 December 2016 

TEHRAN, Dec. 18 (MNA) – Iranian researchers at Amirkabir University have designed and developed brain stimulator transcranial direct current stimulation (tDCS) devices that can be used in treatment of Parkinson's Disease.

Golnaz Baghdadi, Bioelectric PhD student at Biomedical Engineering Department of Amirkabir University of Technology (AUT), told Mehr News that the tDCS device has been developed in Iran for the first time by a team at AUT led by Dr. Farzad Tohidkhah, rector of the Biomedical Engineering Department.

“The brain stimulator tDCS device is used in treatment of depression, on people suffering from attention deficit disorder or patients with Parkinson’s Disease,” she said.

Explaining about the device performance, she said “the device stimulates the brain by delivering a constant, low current to the brain area of interest via electrodes on the scalp. After a few sessions, the patient will start showing signs of improvement.”

She went on to add, “the effects will last up to three to four months, and then the patient needs to go back to the clinic so that the device will be set on a specific dosage to be used by the patient at home.”

“Compared to the foreign version, the Iranian tDCS device is programmable by computer, can store data via a flash drive, has a touch screen for ease of use, and is more affordable,” she said.

Baghdadi maintained that the device is currently at the commercialization stage, adding “tests conducted on the device have yielded positive results and it is now ready to receive orders.”

MS/3851603

http://en.mehrnews.com/news/122084/Iran-builds-brain-stimulator-tDCS-device

Jean Shepard broke down barriers in country music, later battled Parkinson’s Disease

BY GABE MIRKIN   DECEMBER 18, 2016

Jean Shepard

On Sept. 29, 2016, country music lost one of its all-time greats.  Most of you have heard Jean Shepard singing “A Dear John Letter” with Ferlin Husky, the first post-World War II record by a female country singer to become the number one country song and sell more than a million records.  It tells of a girl who writes to her soldier boyfriend fighting in Korea that she is going to marry his brother who did not have to go to war.  

In 1955, Shepard joined the Grand Ole Opry and continued to perform there for 60 years. In later life, she was incapacitated by Parkinson’s disease and the associated heart problems that eventually killed her at age 82.

Early Years

Shepard was born in 1933 into incredible poverty during the great depression, in Pauls Valley, a small “dust bowl” town in Oklahoma where people were starving.  Her parents had 10 children to support with no way to earn a real living, so they moved to Visalia, California, about 80 miles north of Bakersfield.   Their only entertainment there was listening to the Grand Ole Opry on a battery-powered radio on Saturday night.   When Shepherd was 15, her wonderful supportive parents sold their furniture to pay for a bass fiddle so she could sing and play in an all-girls band called The Melody Ranch Girls.  

She met country music star Hank Thompson and told him she wanted to be a country star. He told her, “There ain’t much room in this business for a woman country singer.”  She recalled telling him that, “There weren’t nothing going to stop me doing what I wanted to do, which was singing traditional country music the way it’s supposed to be sung.” He was so impressed with her that he called Capitol Records.  True to form, they were not interested in her because she was a woman, but Hank pressured them to listen to her sing and they liked what they heard.  

Her second record, “Dear John Letter,” a duet with Ferlin Huskey, became her most famous and best-selling record.  At that time, she was under age 21 and therefore a minor who could not travel across state lines without her parents. To go on tour to publicize her records, her parents had to “give her up” and make Ferlin Huskey her legal guardian.  At age 22, she sang on ABC-TV’s nationally-telecast Ozark Jubilee and at the Grand Ole Opry in Nashville.  At age 31, she came out with her second most popular song hit, “Second Fiddle (To an Old Guitar)”.

Jean Shepard

A few years before her death, TV singer Blake Shelton said that fans of traditional country music were “old farts and jackasses”.  She replied, “We’ve got a young man in country music who has made some pretty dumb statements lately that traditional country music is for old farts and jack-you-know-whats.  Well, I guess that makes me an old fart. I love country music. I won’t tell you what his name is — but his initials is BS — and he’s full of it!”

Marriages and Children

She met fellow country singer Hawkshaw Hawkins and married him in 1960.  In 1963, Hawkins died in a plane crash that also killed country singers Patsy Cline and Cowboy Copas. At the time of the crash, she was eight months pregnant with their second son.  In 1968, she married another country singer, Benny Birchfield, and had another son.  They remained married until her death.

Her Later Years

In 2011, at age 78, she was voted into the Country Music Hall of Fame. Her autobiography, “Down Through the Years”, was published in 2014.  In 2015 at age 82, she celebrated her 60th year with the Grand Ole Opry and retired.  She was already suffering from Parkinson’s disease and went downhill quickly.  She died on September 29, 2016, at age 82.

Parkinson’s Disease 

I do not have access to Shepard’s medical records, so the following is a general explanation of Parkinson’s disease and its current treatments. 

Parkinson’s is a disease that usually starts in people over the age of 50 and occurs more frequently with increasing age. The cause is not known.  

A part of the brain called the substantia nigra makes dopamine, a chemical that sends messages from the brain across nerves in the spinal cord to control muscles.  In Parkinson’s disease the substantia nigra is damaged so the body lacks dopamine, which blocks messages from the brain to the muscles. 

Symptoms

The symptoms of Parkinson’s disease come from this blockage of messages from the brain to the muscles:

• Slowness of movement – a shuffling walk, difficulty in starting, stopping and turning easily 

• Stiffness of muscles – for example, the arms do not swing as they ordinarily do during walking

• Shaking (tremor), primarily while at rest.

A person with Parkinson’s disease may have:  

• Reduced facial expressions such as smiling or frowning 

• Reduced blinking

• Difficulty with fine movements such as fastening buttons or tying shoes

• Difficulty writing

• Difficulty with balance, causing falls

• Slowed speech

• Swallowing problems, causing drooling

• Tiredness, aches and pains

• Constipation

• Bladder problems and incontinence

• Hallucinations

• Abnormal sweating

• Sexual difficulties

• Loss or distortion of sense of smell

• Sleeping problems 

• Weight loss

• Depression

• Anxiety

• Compulsive behaviors 

Current Treatment

Since the problems are caused by lack of dopamine, the treatment is to raise dopamine levels in nerves.  At first the drugs that raise dopamine are very effective, but over time, all of the drugs that are currently available lose their effectiveness and the doctor must prescribe ever-increasing doses and combinations of drugs.

There is evidence that some of the drugs used to treat Parkinson’s disease (pergolide and cabergoline) are associated with a higher risk of heart valve damage and lesser evidence that these drugs are associated with increased risk for heart failure in Parkinson’s patients (CNS Drugs.  Dec, 2015;29(12):985-98).

https://www.villages-news.com/jean-shepard-broke-barriers-country-music-later-battled-parkinsons-disease/