Neuroscience is Advancing, So How Far Off Are We From a Successful Head Transplant?

NEUROSCIENCE NEWS  MAY 5, 2018
Source: The Conversation.

With the first head transplant scheduled for 2018, many neuroscientists are skeptical the procedure will be a success. A new article questions if scientists, and the general population, will be ready for the procedure. What does it mean for the future of mankind?

Many unknowns also exist with head transplants. While Italian neurosurgeon Professor Sergio Canavero has claimed that he will carry out the first human head transplant in 2018, many neuroscientists are sceptical. NeuroscienceNews.com image is adapted from The Conversation news release.

In the 1983 film The Man with Two Brains, Steve Martin’s character falls in love with the disembodied brain of a woman named Anne.

But what once sat in the realm of movies and science fiction novels now seems slightly more plausible. Recent advances in neuroscience have lead to human cells being grown into “mini brains” in the lab, and brains of decapitated pigs being “kept alive” for a day and a half.

So are we closer to a time when brains may be able to function in isolation from a body – leading to head transplants or even brains frozen and brought back to life in the future?

I think such possibilities are a long way off.

A brain without a body

Professor Nenad Sestan of Yale University reported in March that he and his team restored blood circulation to the brains of decapitated pigs, and kept brain cells alive and functioning for up to 36 hours.

This technology, called “BrainEx”, restores circulation by connecting the brain to a series of pumps and heaters that pump artificial blood and carry oxygen to key regions, including areas deep inside the brain. This allows even microcirculation – the flow of blood to the smallest blood vessels and cells – to be restored.

This work opens up a number of potential future research avenues, including the ability to test new treatments for Alzheimer’s disease and other neurological conditions.

A more developed area of neuroscience is the generation of brain organoids, “mini brains” grown from human stem cells and kept alive in the laboratory.

These organoids mimic features of the developing brain, allowing researchers to undertake research into conditions such as autism spectrum disorders and schizophrenia.

Are the brains really alive?

Sestan believes his approach to keeping pig brains alive is likely to work in other species, including primates.

But what might keeping brains “alive” mean for the individual? Might it be possible for the disembodied brain to retain its consciousness and memory, devoid of any sensory input or ability to communicate?

Monitoring of the pig brains via a technique known as EEG showed no sign of complex electrical activity indicating thought or sensation. This could be due to lowered activity or damage of brain cells during the procedure.

But some research has indicated that, even when the EEG is a flat line, there may still be some activity in deep brain structures such as the hippocampus, a brain area critical for memory.

The question of measuring activity is also relevant to the brain organoids. With improvements in techniques, there is the potential that organoids may become more complex. Although it’s still very unlikely, it’s possible they may take on aspects of higher-order brain functioning, such as feeling pleasure and pain, storing memories, or even experiencing some degree of consciousness.

What is consciousness?

Consciousness is one of the most difficult brain phenomena to explain, and a question that modern neuroscience is just beginning to make progress on. It’s even difficult to actually define what consciousness is.

Australian philosopher David Chalmers has referred to these challenges as the “hard problem” of consciousness – understanding why consciousness occurs.

Multiple theories and models of consciousness have been proposed, and experts tussle back and forth about which is most accurate. Some critics even claim that most theories of consciousness are “worse than wrong” – they don’t actually explain anything.

Physiologically, the EEG is still the most sensitive measure to indicate consciousness. When an individual is awake and alert, the EEG is “activated”, characterised by low voltage, high frequency fast brain waves.

When there is a loss of consciousness, brain waves slow down and get higher in amplitude as brain cells alter their firing rates.

Parts of the brain thought to be involved in consciousness include the rear part of the cerebral cortex (at the surface), and also deeper structures such as the brainstem. EEG activity in specific areas of the brain may be one of the most effective ways to discriminate between conscious and unconscious individuals.

Can a brain without a body be conscious?

Currently we are a long way from experimental models of the human brain – such as brain organoids or disembodied brains – being conscious. However, we could need to confront such a possibility as technology advances and models become more sophisticated.

Indeed, the hope of this has led to initiatives such as cryogenically preserving (freezing) brains, and even proposed head transplants.

But I wouldn’t rush out and put my name down for these procedures just yet. In the case of cryogenically preserving tissue, evidence has yet to demonstrate that all areas of the brain are reached with the antifreeze used to protect tissue from fracturing at the extremely low temperatures.

Even if the tissue can somehow be protected from freezing damage, warming that tissue back up again is likely to result in further extensive problems. This would make it difficult, if not impossible, to ever return the brain to a conscious state – and that’s all before you deal with the issues inherent in actually transplanting the brain into another body.

Many unknowns also exist with head transplants. While Italian neurosurgeon Professor Sergio Canavero has claimed that he will carry out the first human head transplant in 2018, many neuroscientists are sceptical.

There are a host of issues with such a procedure. There’s the possibility of rejection of the head by the donor body, and the difficulty of connecting the spinal cord to the brain in a way that the brain can control the donor body. Additionally, even if it did work in a physical sense, there are problems around how such a procedure might affect the individual’s sense of self-awareness or consciousness.

Where should the field go from here?

There are many ethical concerns linked to the idea of brains in culture or removed from bodies – including what protections are necessary, how to address issues around consent, ownership and post-research tissue handling, and even how to define death.

In late April, 17 experts in neuroscience, stem-cell biology, ethics and philosophy published an editorial in Nature outlining many of the issues that need to be considered and calling for “clear guidelines for research”.

Such conversations also need to be held outside of academic circles and should engage ethics committees, research funding bodies, and, most importantly, the wider public.

While there has never been a more exciting time to work in neuroscience, it is critical that proper safeguards be put in place now as models continue to advance.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Funding: Lyndsey Collins-Praino receives funding from the NeuroSurgical Research Foundation and the Commercial Accelerator Scheme.

Source: Lyndsey Collins-Praino – The Conversation

Publisher: Organized by NeuroscienceNews.com.

Image Source: NeuroscienceNews.com image is adapted from The Conversation news release.

http://neurosciencenews.com/head-transplant-success-8973/

Parkinson's disease sufferers able to sleep through brain surgery after breakthrough

May 5, 2018

PHOTO: Grant Rowe's Parkinson's procedures have been life-changing for both him and his wife Lisa. (ABC News: Danielle Bonica)

Parkinson's disease sufferer Grant Rowe says it is a strange experience to be awake while a surgeon "is digging around" in his head, inserting electrodes the size of a grain of rice in his brain

Mr Rowe was diagnosed with the degenerative illness 10 years ago and has been undergoing deep brain stimulation (DBS), which helps reduce his symptoms of tremors, stiffness and slowed movement.

The procedure requires pinpoint accuracy so patients have had to remain awake, allowing surgeons to test their responses to make sure they are in the right spot.

If it's not, the treatment can be less effective or cause unwanted side-effects.

"It's a surreal experience being awake for surgery, cracking jokes with your doctor while he's digging around in your head," Mr Rowe said.

But being conscious during the surgery can be confronting for some.

Wesley Thevathasan, a clinical neurologist with the Bionics Institute, said many people who are eligible to have the procedure do not, because they find the idea too much to handle.

"Probably only 10 per cent of people who would benefit greatly from DBS actually get it," he said.

PHOTO: Dr Wesley Thevathasan said the discovered brainwave makes surgery much more accurate. (ABC News: Danielle Bonica)

But a breakthrough by researchers from the Bionics Institute and Melbourne's St Vincent's and Austin hospitals will now allow surgery to be performed while the patient is asleep.

While studying the brainwaves of 17 patients, researchers discovered a unique brain signal that could be used to guide the surgeon.

"For the surgery to be successful we need to hit the top of the 'grain of rice' — if we miss it by a millimetre we get away with it, if we miss it by 2mm the operation is a failure and we would have to do it again," Dr Thevathasan said.

"If you're driving a car you want to know what speed you're going.

"We've got these little signals that are absolutely miniscule … and this signal that we found is many orders of magnitude bigger, and therefore makes an ideal marker of where we are and if it's working."

Parkinson's occurs when the brain does not produce enough dopamine, which helps relay messages between cells in the brain.

The electrodes inserted during surgery stimulates an area of the brain — similar to a pacemaker in the heart — allowing the dopamine that is naturally produced to be used elsewhere.

PHOTO: Only 10 per cent of sufferers who would benefit from deep brain stimulation get the procedure, Dr Thevathasan says. (ABC News: Danielle Bonica)

When 'normal' feels like a miracle

Mr Rowe said he had been struggling before the treatment: "I basically felt old every day."

The 49-year-old dad said the DBS procedure had improved the quality of his daily life."I'm basically on no medication … because of the surgery," he said.

His wife Lisa said the improvements in her husband had been a relief for both of them.

"The first thing that changed [after treatment] … he wasn't stiff anymore. It's just that whole sense that he's mobile again, his gait is smoother, his walking pace," she said.

"I guess I'm not alert to 'what does he need from me'. I can can be a wife or partner. All of a sudden normal is a miracle, it's a god-send." 

  

Doctors hope the benefits of the breakthrough are twofold: one, it will mean more people will opt to have the surgery, the other could be in further technology improvements.

Currently, the level of stimulation administered to the brain is fixed, meaning it can sometimes be ineffective, or produce side-effects if it is too strong.

There is now hope a new electrode device could be created that can detect changes in the brain signal and respond to a patient's changing symptoms in real time.

http://www.abc.net.au/news/2018-05-05/parkinsons-disease-breakthrough-deep-brain-stimulation/9730850

Dan­cer's brains dis­play brain fre­quen­cies linked to emo­tion and memory pro­cesses

May 4, 2018, University of Helsinki

The change in music was apparent in the dancer's brain as a reflex before they are even aware of it at a conscious level. Credit: 123RF

Neuroscience has studied music for decades, and it has been found to activate both the cortical and deeper brain areas. Neuroscience of dance, instead, is a young but quickly growing field.

In her doctoral dissertation, Master of Science Hanna Poikonen developed methods for understanding the processes that dance generates in the cortex at the Cognitive Brain Research Unit of University of Helsinki. In her research project, she compared the brain functions of professional dancers and musicians to people with no experience of dance or music as they watched recordings of a dance piece.

According to the results, the brain activity of the dancers was different from that of musicians and the control group during sudden changes in the music, long-term listening of music and the audio-visual dance performance.

"The dancers' brains reacted more quickly to changes in the music. The change was apparent in the brain as a reflex before the dancer is even aware of it at a conscious level," Poikonen says.

"I also found that dancers displayed stronger synchronisation at the low theta frequency. Theta synchronisation is linked to emotion and memory processes which are central to all interpersonal interaction and self-understanding."

These results support the earlier findings indicating that the auditory and motor cortex of dancers develops in a unique way.

"Studies of professional dancers and musicians have highlighted the importance of multimodal interaction and motor-related brain regions in cerebral processing of dance and music," Poikonen says.

In her research, she used the novel EEG methods that she had developed: event-related potentials to investigate the influence of fast changes of musical features in the brain in a short timescale and changes in phase synchrony between two electrode channels when investigating cortical dynamics during observation of dance and music over a longer timescale.

These methods could be used in the development and assessment of therapy as well.

"The methods could be applied in estimating the efficiency and developing further expressive therapies, such as dance-movement therapy, as a part of holistic treatment plan for conditions such as Parkinson's disease, dementia, autism, and pain and mood disorders."

More information: Dance on Cortex—ERPs and Phase Synchrony in Dancers and Musicians during a Contemporary Dance Piece: urn.fi/URN:ISBN:978-951-51-42

Provided by: University of Helsinki 

https://medicalxpress.com/news/2018-05-dancer-brains-brain-frequencies-linked.html

There’s more to Parkinson’s than ‘stop and go’

Posted by Nathan Collins-Stanford May 4th, 2018

Researchers have tested a core theory of Parkinson’s disease and found it lacking, which could have implications well beyond Parkinson’s disease itself.

Parkinson’s disease affects around 10 million people worldwide, yet exactly how the disease and treatments for its symptoms work remain mysterious.

The theory in question, known as the rate hypothesis, has it that Parkinson’s results from an imbalance in brain signals telling the body to start and stop moving.

“The idea was there was too much ‘stop’ and not enough ‘go,’ and that’s why there’s difficulty with movement,” says senior author Mark Schnitzer, an associate professor of biology and of applied physics at Stanford University, an investigator at the Howard Hughes Medical Institute, and senior author of the paper in Nature.

But that’s only part of the story, Schnitzer says. In fact, “start” and “stop” signals are more complex and structured than the rate hypothesis suggests, and Parkinson’s disease in part reflects a loss of that complexity and structure.

Neuron tracking

Doctors have known for decades that Parkinson’s involves the loss of neurons in a region of the brain called the substantia nigra, and that the loss affects brain circuits thought to be responsible for initiating and terminating movement.

With that in mind, the rate hypothesis seemed quite reasonable: If there was abnormal neural activity in the start or stop circuits, that could lead to the movement problems associated with Parkinson’s.

But testing that hypothesis proved difficult, because the neurons that make up the two pathways are closely intertwined. To see if the start pathway neurons were in fact suppressed, as the rate hypothesis suggested, while stop pathway neurons were overactive, researchers needed a way to track the activity of individual neurons.

To do so, Schnitzer, research associate Jones Parker, Schnitzer’s former graduate student Jesse Marshall, and colleagues turned to mice that researchers had genetically modified so that neurons in the start and stop pathways would flash green when they were active.

Immediate surprises

The team examined the mice under three distinct conditions: normal healthy conditions; a condition that mimics Parkinson’s disease; and that same Parkinson’s-like condition but this time treated with L-dopa (levodopa), the most common drug for Parkinson’s symptoms.

Then, the team peered into their mice’s brains with miniature, head-mounted microscopes to look for green flashes of light that indicate what the start and stop neurons were up to.

There were surprises almost immediately. “We found all this undiscovered structure” in both pathways, Marshall says. Rather than all neurons in one or the other pathway lighting up at once, as the rate hypothesis would suggest, certain clusters seemed to be associated with certain activities.

In healthy mice, a cluster in the start pathway might light up as a mouse began to turn left, while another in the stop pathway might light up when that mouse finished grooming its tail.

There were more surprises in the mice that mimicked Parkinson’s disease. Although there was less activity in the start pathway, as the rate hypothesis predicted, activity in the stop pathway became unstructured. Rather than suppress particular movements—”stop grooming” or “stop turning left,” for example—the stop pathway now seemed to be suppressing many different movements at once.

Treating those mice with L-dopa restored normal activity in both start and stop pathways, the team found, but things went wrong if the dose was too high. Now, there was less activity in the stop circuit, while activity in the start circuit lost its structure, so that now it would initiate movements somewhat at random rather than in the coordinated way characteristic of healthy mice.

That finding could help explain one of the most common and visible side effects of the treatment of Parkinson’s disease—jerky, uncontrollable movements known as dyskinesia—Schnitzer says.

Beyond Parkinson’s

The idea that Parkinson’s disease affects not just the level but also the structure of activity in start and stop circuits could change how researchers think about Parkinson’s and a number of other diseases—among them Huntington’s disease, Tourette’s syndrome, chronic pain, and even schizophrenia—thought to share a similar underlying mechanism, Parker says.

Beyond understanding those conditions better, the results could ultimately lead to better outcomes for patients with those diseases.

In particular, additional tests comparing L-dopa to two other, less effective Parkinson’s drugs showed how L-dopa fully restored activity in neurons that control movement, while the others did not—hinting that it may be possible to screen new medications by examining their effects on patterns of brain activity, Schnitzer says.

“So what we may have here is a new way for testing and screening new drugs by looking directly at neural circuit activity.”

The Howard Hughes Medical Institute, the Stanford Cracking the Neural Code Program, the Stanford Photonics Research Center, Pfizer, a GG Technologies gift fund and fellowships from Stanford, the Helen Hay Whitney Foundation, the US National Institutes of Health, and the Swiss National Science Foundation funded the work.

Schnitzer is a scientific co-founder of Inscopix Inc., which produces the miniature microscope technology used in the study.

Source: Stanford University

Original Study DOI: 10.1038/s41586-018-0090-6

https://www.futurity.org/parkinsons-disease-theory-stop-go-1749622/

Rabies Virus May Hold Key for Efficient Therapies in Parkinson’s, Study Suggests

MAY 4, 2018    BY JOSE MARQUES LOPES, PHD IN NEWS.

New nanoparticles containing a specific part of the rabies virus may improve brain-targeting therapy in Parkinson’s patients, study suggests.

The research, “Targeted Brain Delivery of Rabies Virus Glycoprotein 29-Modified Deferoxamine-Loaded Nanoparticles Reverses Functional Deficits in Parkinsonian Mice,” was published in the journal ACS Nano.

A common feature of Parkinson’s is the accumulation of iron in the brain, which causesoxidative damage and neuronal death in the substantia nigra, a critical area in movement control. This iron build-up has led to the use of metal-grabbing compounds such as deferoxamine (DFO), which binds to iron and aluminum. However, high doses are required to overcome the compound’s limited ability to enter the brain.

The rabies virus causes encephalomyelitis, a rapidly progressive infection in the brain and spinal cord. To cross the blood-brain barrier, which separates the brain from the circulating blood, the virus must first trick the nervous system. This natural viral capacity is a strategy of interest for drug development, which may enable researchers to lower the dose of DFO needed to exert effects in the brain, while reducing its side effects.

A team of Chinese and Australian researchers created a nanoparticle (tiny particle) system containing a part of the rabies virus (glycoprotein 29) that binds to a specific receptor in nerve cells and enable DFOs delivery into the brain.

After experiments in cells grown in the laboratory to evaluate the nanoparticles’ efficiency, its blood-brain barrier permeability, and its pharmacological profile, researchers tested the particles in a Parkinson’s mouse model.

“This nanoparticle system showed satisfactory efficiency in intracerebral delivery of DFO and could be readily internalized by neuron cells,” researchers wrote.

Intravenous injection of these iron-grabbing nanoparticles boosted the accumulation of DFO in the mouse brain, reduced brain iron levels, eased oxidative stress and neuronal death in the substantia nigra, and reversed Parkinson’s neurobehavioral deficits.

Importantly, the scientists did not observe relevant side effects in the brain or other major organs.

“This DFO-based nanoformulation holds great promise for delivery of DFO into the brain and for realizing iron chelation therapy in [Parkinson’s] treatment,” they wrote.

Because all of the components in the nanoparticle system are already approved to be used in the clinic, the investigators are now looking to initiate human trials.

https://parkinsonsnewstoday.com/2018/05/04/rabies-virus-may-hold-key-for-efficient-therapies-in-parkinsons-study/

Targeting Enzyme in Immune Cells of Brain May Slow Parkinson’s Progression, Study Suggests

MAY 4, 2018  BY ALICE MELÃO 

Blocking the activity of an enzyme found in immune cells of the brain may prevent the degeneration and death of nerve cells seen in Parkinson’s disease, new research shows.

The study “Upregulation of HDAC2 in Laser Capture Nigral Microglia in Parkinson’s Disease,” was published in Neurobiology of Aging.

The enzyme being studied in this work, called HDAC2, regulates a critical cellular mechanism known as epigenetics. This is a mechanism that controls which genes are available to be read and translated into active proteins, and which genes are silenced and not available.

Because of its key role, HDAC2 — as well as other enzymes of its family — are seen as potential therapeutic targets for several  neurodegenerative diseases. But the relevance of HDAC2 to Parkinson’s is not clear.

Arizona State University-Banner Neurodegenerative Disease Research Center researchers, along with collaborators at Jiao Tong University School of Medicine in China, analyzed the levels and activity of HDAC2 in brain tissue samples from Parkinson’s patients and healthy controls.

The team used an advanced technique called laser captured microdissection, which allows the selection and separation of specific cells within a tissue sample.

Brain immune cells, called microglia, and dopamine-producing nerve cells collected from Parkinson’s patient samples were found to have high levels of HDAC2 compared to the levels of these cells in healthy samples.

Interestingly, HDAC2 levels correlated with the amount of LN3 — a marker of microglia activity — in the Parkinson’s samples but not in the controls. This suggests that HDAC2 may be linked to the greater pro-inflammatory and abnormal (deregulated) activity of microglia, as they transition from protective brain cells to ones that attack and damage healthy neurons.

To further test this hypothesis, the team used experimental cell lines that reproduced the behavior of microglia, the brain’s resident immune cells, and were chemically pushed into a pro-inflammatory state.

These experimental cells showed increased levels of HDAC2, similar to the pattern found in Parkinson’s patients. However, this effect was only observed when cells were exposed to higher levels of the chemical activator, suggesting that brain’s immune cells “may have an inflammatory threshold that must be met” before significant differences in HDAC2 levels are achieved, researchers wrote.

“It has been known for some time now that within pro-inflammatory environments, like the substantia nigra in Parkinson’s disease, microglia are responsible for the constant upregulation and release of neurotoxic cytokines,” Diego Mastroeni,  a study co-author and an assistant research professor in the ASU School of Life Sciences, said in a university news article.

These findings support HDAC2 as a specific target “that may be inhibited to reduce the expression of genes associated with neuroinflammation,” Mastroeni said. “The key will be targeting HDAC2 gene expression levels specifically in substantia nigra’s microglia.”

https://parkinsonsnewstoday.com/2018/05/04/targeting-hdac2-enzyme-in-brain-immune-cellsmay-help-slow-parkinsons-progression-study-says/

A gut bacterium's guide to building a microbiome

May 4, 2018 by Lori Dajose, California Institute of Technology

An electron microscopy image of a section of the mouse gut, showing B. fragilis aggregating close to the epithelial cells that make up the lining of the gut. Credit: Mazmanian laboratory

The mammalian gut is warm, moist, and incredibly nutrient-rich—an environment that is perfect for bacterial growth. The communities of "good bacteria" in the gut, commonly referred to as the microbiome, are vital partners for the body, helping to digest fiber, extract nutrients, and prevent various diseases. We are all familiar with the immune responses and illnesses that ensue from bad, or pathogenic, bacteria entering the body—so, if the immune system evolved to repel microbes, then how do mammals maintain harmonious relationships with the beneficial bacteria in the gut?

Now, new research from Caltech illustrates how a particular species of beneficial bacteria actually harnesses the body's immune response so that it can settle down comfortably in the gut.

The work was done in the laboratory of Sarkis Mazmanian, Luis B. and Nelly Soux Professor of Microbiology and Heritage Medical Research Institute Investigator. A paper describing the research was published online on May 3 in the journal Science.

Led by graduate student Gregory Donaldson, researchers in the Mazmanian laboratory chose to examine a microbe called Bacterioides fragilis. The particular species is found abundantly in the large intestines of many mammals, including humans, and was previously shown by the Mazmanian lab to protect mice from certain inflammatory and neurological disorders such as inflammatory bowel disease and multiple sclerosis. Interestingly, though there are multiple strains of B. fragilis, healthy people form a long-term, monogamous relationship with only a single strain.

"Studies by other labs have shown that most people carry the same strain of B. fragilisthroughout their lives," says Donaldson. "We wanted to understand at a molecular level how these bacteria are able to colonize the gut in a stable, long-term way."

First, the researchers aimed to examine B. fragilis's symbiotic relationship with the gut by physically looking at the locations where the bacteria reside. Using electron microscopy imaging on samples of mouse intestines, the team was able to see that B. fragilisclumps together in aggregates deep within the thick layer of mucus lining the gut, nestled close to the epithelial cells that line the surface of the intestine. Donaldson and his collaborators theorized that this spatial niche is necessary for a single species to settle in and establish a stable foothold.

The team next aimed to determine what mechanisms allow B. fragilisto colonize such a niche within the gut. They found that each B. fragilisbacterium is encased in a thick capsule made of carbohydrates. The capsule is typically associated with pathogens (bad bacteria) attempting to cloak themselves from recognition by and attack from the body's immune system. Mutant bacteria lacking this capsule cannot aggregate and do not inhabit the mucosal layer. Thus, the researchers theorized that capsular carbohydrates are necessary for B. fragilisstrains to monopolize their niche in the gut.

Mucus (green) coating the intestinal surface. Credit: Gregory Donaldson (Caltech)

Because bacterial capsules were known to be related to an immune response in pathogenic bacteria, Donaldson and Mazmanian hypothesized that there may also be an immune response to the B. fragilis capsule. Indeed, they found that antibodies, immune proteins that grab onto and mark specific bacteria or viruses for other immune cells to engulf and destroy, were binding to the B. fragilis capsule in the intestine. One particular kind of antibody, immunoglobulin A or IgA, is found throughout the gut—in fact, it is the most abundantly produced type of antibody in humans—but its specific functions have been enigmatic.

Normally, an antibody response means imminent death to pathogenic bacteria. But curiously, IgA does not negatively affect most of the bacteria that normally live in the gut. In the case of B. fragilis, the researchers found, it actually helped the bacteria stick to epithelial cells. Furthermore, in mice that lacked IgA, the bacterium was less successful at colonizing the surface of the intestine and maintaining long-term stability. 

The team believes that this IgA response to the B. fragilis capsule helps anchor the bacteria to the epithelial surface, thus providing an advantage.

"It is surprising to find that an immune response actually helps beneficial bacteria to thrive, which in turn helps the host thrive," says Donaldson. "The study of immunology has mainly been in the context of pathogenic bacteria. But there are trillions of bacteria in the gut, and most of the time none of them are making you sick. Our study shows that there is active immune recognition of these bacteria, but it helps rather than hinders them. This suggests that the immune system is more than just a defense system and antibodies are more than just weapons."

In future work, the researchers plan to study how the gut's antibody response arises in the first place and why it helps B. fragiliswhile other antibodies hurt bacteria. Ultimately, this work could be used to improve colonization by other beneficial bacteria, as through the use of probiotics.

"Over the past decade, many studies have profiled the gut microbiome in a variety of diseases, lifestyles, geographies, and following birth," says Mazmanian. "We've learned that the community composition of the microbiome correlates with particular conditions—for example, altered microbiome configurations may contribute to inflammatory bowel disease, autism, and Parkinson's disease. What has remained largely unknown is how a microbiome is established and maintained in the first place. Our study reveals a molecular mechanism by which specific beneficial bacteria actively promote long-term intestinal colonization by engaging and co-opting the immune system, rather than trying to evade it as pathogens do. This discovery may lead to new ways to correct microbiome imbalances, and perhaps to prevent and treat a variety of human disorders."

The paper is titled "Gut microbiota utilize immunoglobulin A for mucosal colonization."

More information: G. P. Donaldson et al. Gut microbiota utilize immunoglobulin A for mucosal colonization, Science (2018). DOI: 10.1126/science.aaq0926 

Journal reference: Science

Provided by: California Institute of Technology

https://medicalxpress.com/news/2018-05-gut-bacterium-microbiome.html

LRRK2 Worthy Target of Research into Parkinson’s Therapies, Study Suggests

MAY 3, 2018 BY ANA PENA 

A perspective article summarizes what researchers have learned so far on the role of LRRK2 mutations in the development of Parkinson’s disease, and recommends the enzyme as a target for therapy development.

The report, “LRRK2 kinase in Parkinson’s disease,” was published in the journal Science.

Although the vast majority of Parkinson’s cases are idiopathic, or of unknown cause, LRRK2mutations — the leading genetic cause of this disease — account for about 1 to 2 percent of all cases. Mutations in this gene increase the risk of developing Parkinson’s due to an LRRK2-increased risk of neuronal death.

About 20 LRRK2 mutations have been linked with the disease, and its incidence can be higher in some populations such as the Ashkenazi Jews and North African Berbers.

The LRRK2 gene codes for the enzyme leucine-rich repeat kinase 2 (LRKK2), a protein that modifies other proteins’ activities, including signaling, replication, and gene expression.

All LRRK2 disease-causing mutations lead to higher LRKK2 enzyme activity; as such, researchers believe that inhibiting or blocking its activity can be used as a potential therapeutic target.

In fact, two LRRK2 inhibitors are currently being evaluated to treat Parkinson’s in two Phase 1 trials. The experimental therapies, called DNL-201 and DNL-151, are being developed by Denali Therapeutics. So far, DNL201 has stopped an average 90 percent of LRRK2 kinase activity at its highest concentration. When the drug’s levels dropped to the lowest concentration, it still inhibited on average 50 percent of such activity.

Studying the effects of LRRK2 mutations also provides an opportunity to better understand how Parkinson’s disease unravels, the study notes.

Recent advances support that LRRK2 modifies a group of proteins, called Rab GTPases, that regulate diverse cellular processes. 

These proteins play important roles in immune responses and vesicular trafficking — the transport and recycling of materials inside the cell through a system of vesicles.

Disruption of RAB-related transport may also promote accumulation of alpha-synuclein aggregates inside neurons, a hallmark of Parkinson’s disease.

LRRK2 is also thought to be linked to inflammation, a process that plays an important part in disease development. LRRK2  is highly expressed  in several immune system cells, including macrophages,  monocytes, and neutrophils. 

“Research indicates that, in early  life, increased LRRK2 activity may protect against opportunistic  pathogenic infection but then later increases the risk of developing Parkinson’s disease,” the researchers write.

LRRK2-associated Parkinson’s closely resembles idiopathic disease in terms of its late age of onset and  symptoms. But several factors seem to influence the ability of LRRK2 mutations to cause disease, including age and the type of mutation.

People carrying some types of mutations, such as G2019S, may never develop Parkinson’s, while nearly all of those bearing the R1441G mutation eventually will. 

One case report in twins carrying the same LRRK2 mutation found only one developed Parkinson’s. This highlights the importance of environmental factors and lifestyle (smoking, exercise, diet), as well as the gut microbiome and infection in the development of LRRK2-dependent Parkinson’s.

“However, for now, the most exciting question will be whether LRRK2 inhibitors have disease-modifying effects in PD patients with LRRK2 mutations,” the researchers wrote.

The authors stress that preclinical studies in animal models indicate potential toxicity of LRRK2 inhibitors to the lungs and kidneys, and recommend special attention be taken to monitor toxicity in these organs in human clinical trials. 

Given the role of LRRK2 in fighting infections, it will also be important to establish whether blocking LRRK2 increases the risk of opportunistic infections. But, overall, the scientists believe that “LRRK2 is a possible therapeutic target for Parkinson’s disease.”

https://parkinsonsnewstoday.com/2018/05/03/parkinsons-lrrk2-mutation-potential-therapy-target-study-suggests/