Parkinson's therapy creates new brain circuits for motor function, study finds

November 28, 2018, Northwell Health's Feinstein Institute for Medical Research

Immunohistochemistry for alpha-synuclein showing positive staining (brown) of an intraneural Lewy-body in the Substantia nigra in Parkinson's disease. Credit: Wikipedia

Scientists have uncovered that an emerging gene therapy for Parkinson's disease creates new circuits in the brain associated with improved motor movement. 

These findings, published today in Science Translational Medicine by Feinstein Institute for Medical Research Professor David Eidelberg, MD, and his team, explain the therapeutic mechanisms involved in the emerging Parkinson's gene therapy called AAV2-GAD. These findings help the scientific and clinical communities by progressing AAV2-GAD into clinical trials while providing a better understanding about Parkinson's disease treatment response and effectiveness.

Parkinson's disease is the second most common neurodegenerative disease in the United States. Patients often experience tremors, slowness of movement (bradykinesia), rigidity and impaired balance and coordination, resulting in difficulty walking, talking or completing simple daily tasks. Current therapies and medications for Parkinson's disease aid with symptoms, but do not slow the underlying neural degeneration. 

Gene therapy, which injects genes into cells to correct abnormalities in brain function, is an emerging therapeutic approach for neurodegenerative disorders such as Parkinson's disease. Recent phase 2 clinical trials showed that delivering the gene glutamic acid decarboxylase (GAD) into a part of the brain called the subthalamic nucleus had therapeutic effects for patients. Dr. Eidelberg's examination of the mechanisms of AAV2-GAD therapy discovered that the therapy's mechanism of action is unique compared to other Parkinson's treatments.

"Current Parkinson's disease therapies act on the abnormal disease network in the brain and often stop working over time as the body builds a tolerance. What we observed with AAV2-GAD therapy is quite the opposite," said Dr. Eidelberg who is the senior author of the paper. "We found that AAV2-GAD leads to the formation of new neural pathways in the brain, connecting the subthalamic nucleus to other motor regions, thereby improving motor symptoms for as long as 12 months."

In the study, Dr. Eidelberg and his team analyzed metabolic PET scans from 15 Parkinson's disease patients who received the gene therapy and 20 who were randomized to sham surgery and then rescanned six and 12 months after surgery.

 What they found was that those who received the gene therapy started to form new brain connections, which matured by the end of the 12-month study. Dr. Eidelberg's team plans to use the appearance of these new circuits as a treatment biomarker in an upcoming phase 3 clinical trial for this new intervention for Parkinson's disease.

"Dr. Eidelberg's research in Parkinson's disease has opened important new avenues for mapping brain networks that are fundamental to understanding debilitating movement disorders," said Kevin J. Tracey, MD, president and CEO of the Feinstein Institute. "This latest work mapping the therapeutic benefit of AAV2-GAD gene therapy is a major next step to further refining therapies that combat the root causes of the condition."

More information: M. Niethammer el al., "Gene therapy reduces Parkinson's disease symptoms by reorganizing functional brain connectivity," Science Translational Medicine (2018). stm.sciencemag.org/lookup/doi/ … scitranslmed.aau0713

Journal reference: Science Translational Medicine

Provided by: Northwell Health's Feinstein Institute for Medical Research 

https://medicalxpress.com/news/2018-11-parkinson-therapy-brain-circuits-motor.html

More Oregonians sharing end-of-life wishes with POLST

November 28, 2018 by Franny White, Oregon Health & Science University

More Oregonians are making their end-of-life wishes known through forms known as Physician Order for Life-Sustaining Treatment, or POLST, according to research published in the Journal of Palliative Medicine.

After comparing a database of Oregon POLST forms and state death certificates, OHSU researchers found 45 percent of Oregonians who died between 2015 and 2016 had filled out a POLST form, compared with about 31 percent between 2010-11. Oregon first started using POLST forms in the 1990s, but a central, statewide POLST database wasn't established until 2009.

Researchers also found how people are using the form is changing. The length of time between when people filled out the form and died increased from an average of five weeks to 21 weeks.

We learned that patients with Alzheimer's and Parkinson's often complete POLST forms earlier in their disease then their final year of life, according to study co-author Susan Tolle, M.D., director of the OHSU Center for Ethics in Health Care and professor of medicine (general internal medicine and geriatrics) in the OHSU School of Medicine.

While the oldest Oregonians increased their POLST usage the most, there was also a rise in POLST use by middle-aged Oregonians. The total number of people aged 95 and older who died and used POLST forms increased 83 percent between 2010-11 and 2015-16, while those aged 45 to 64 used the forms about 19 percent more during the same timeframe.

The data also indicated more Oregonians who die are indicating via POLST that they want more extensive medical care. For example, about 13 percent of POLST forms completed by those who died between 2015-16 requested CPR, compared with about 8 percent in 2010-11. And about 11 percent in 2015-16 requested full medical treatment, compared with about 6 percent in 2010-11. Other options on the form include declining resuscitation and requesting limited treatment or comfort-focused care.

The POLST form was created after a group of ethics leaders convened by OHSU to ensure the end-of-life health care wishes of those with advanced illness or frailty would be followed. POLST-like programs have been adopted or are in development in all 50 states and Washington, D.C., and they are associated with reducing unwanted hospitalizations near the end of life.

Separate from POLST, advanced directive forms share a patient's end-of-life philosophy and preferences, but they do not provide actionable medical orders for emergency medical service personnel such as EMTs to follow.

More information: oregonpolst.org/form-details/

https://medicalxpress.com/news/2018-11-oregonians-end-of-life-polst.html

Antibiotic could protect against neurodegenerative diseases during aging

 November 28, 2018, eLife

Caenorhabditis elegans. Credit: Wikipedia

An antibiotic, minocycline, can increase the lifespan of roundworms by preventing the build-up of proteins during aging, a study in the open-access journal eLifereports.

Protein aggregation causes several progressive age-related brain diseases, including amyotrophic lateral sclerosis, Alzheimer's, Parkinson's and prion disease. This study shows that minocycline prevents this build-up even in older animals with age-impaired stress-response pathways.

The number of proteins in a cell is balanced by the rate of protein manufacture and disposal, called proteostasis. As we age, proteostasis becomes impaired. "It would be great if there were a way to enhance proteostasis and extend lifespan and health, by treating older people at the first sign of neurodegenerative symptoms or disease markers such as protein build-up," says lead author Gregory Solis, a graduate student at Scripps Research, US. "In this study, we investigated whether minocycline can reduce protein aggregation and extend lifespan in animals that already have impaired proteostasis."

The team first tested 21 different molecules known to extend lifespan in young and old Caenorhabditis elegans (C. elegans) worms. They found that all of these molecules prolonged the lives of young worms; however, the only drug that worked on the older worms was minocycline.

To find out why, they looked at whether minocycline had any effect on protein aggregation in the worms. They treated young and old worms with either water or minocycline and then measured two proteins called α-synuclein and amyloid-β, which are known to build up in Parkinson's and Alzheimer's disease, respectively. Regardless of the worms' age, those treated with minocycline had reduced aggregation of both proteins as they grew older without even without the activation of stress responses.

The team next turned their attention to the mechanism behind this discovery. First, they looked at whether minocycline switches on stress-signalling proteins that are impaired in older worms, but they found the drug actually reduces their activity. Next, they studied whether it turns off the cell's protein-disposal processes, but this was not its mode of action either.

When they used a chemical probe to see how minocycline affects the major protein-regulating molecules in the cell, it revealed that minocycline directly affects the protein-manufacturing machinery of the cell, known as the ribosome. This was true in worms, as well as mouse and human cells.

Finally, the team used worms with increased or decreased protein-manufacturing activity and studied how this altered the effect of minocycline on protein levels and lifespan. As predicted, in mutant worms where protein manufacturing was already decreased, they found that a lower dose of minocycline was needed to further reduce protein levels and extend lifespan. In worms where protein manufacturing was increased, the opposite was seen. This suggested that minocycline extends lifespan by controlling the rate of protein manufacturing at the ribosome.

"We have identified minocycline as a drug that can extend lifespan and improve protein balance in already-aging worms," concludes Michael Petrascheck, Ph.D., senior author of the paper and Associate Professor at Scripps Research. "Our study reveals how minocycline prevents protein aggregation and lays the foundations for drug-development efforts aimed at optimising this already-approved drug for a range of neurodegenerative diseases."

More information: eLife, DOI: 10.7554/eLife.40314

Journal reference: eLife

Provided by: eLife

https://medicalxpress.com/news/2018-11-antibiotic-neurodegenerative-diseases-aging.html

On the trail of rare genetic disease, scientists uncover key immune regulator

November 27, 2018, The Scripps Research Institute

a, An enzyme-coupled assay that begins with ABHD12-mediated hydrolysis of 17:0 lyso-PA, which is followed by glycerol-3-phosphate oxidase (GPO)-mediated generation of H2O2, and culminates in the horseradish peroxidase (HRP)-mediated production of the fluorescent compound resorufin. b, Kinetic performance of the enzyme-coupled HTS assay with membrane lysates from ABHD12- or mock-transfected HEK293T cells. The Z′ and S/B values at 45 min were 0.87 and 3.0, respectively. THL (10 µM) was used as a control ABHD12 inhibitor. c, Screening data for the Maybridge HitFinder collection of 16,0000 compounds. Compounds showing > 50% inhibition are marked in red (198 total). The screen was performed once. d, Structure of the hit compound DO130. e, IC50 value for inhibition of lyso-PS hydrolysis activity of ABHD12 by DO130 measured using ABHD12-transfected cell lysates with 17:1 lyso-PS substrate (100 µM, 20 min, 37 °C). Data represent average values ± s.d. (n = 3 independent experiments). Credit: Nature Chemical Biology (2018). DOI: 10.1038/s41589-018-0155-8

Scientists at Scripps Research have found an important immune system-regulating protein that in principle could be targeted to treat cancers and chronic viral infections.

The scientists, in a study published November 12 in Nature Chemical Biology, set out to determine the function of a protein, ABHD12, whose absence causes a rare genetic disease featuring a host of brain and nerve problems.

The researchers found that ABHD12 normally acts as a powerful "brake" on the immune system to keep it from becoming harmfully overactive. Mice engineered without the protein have signs of elevated inflammation, and their immune systems are more likely to overreact to a viral infection.

The discovery suggests that the absence of ABHD12 in people with mutant versions of its gene may cause neurological disease at least in part via excessive immune activity. It also indicates that ABHD12 may be a useful target for drugs that boost the immune system—for example against cancers and viruses that normally persist by shutting down people's immune defenses.

"This is a good example of how the study of a rare genetic disease can reveal a pathway that plays a key role in human biology," says study co-senior author Benjamin Cravatt, professor and chair of the Department of Chemical Physiology at Scripps Research.

The rare disease in this case is a mix of progressive brain, peripheral nerve, and eye problems that scientists have given the acronym PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract). Since 2010, researchers have known that PHARC is caused by gene mutations that prevent ABHD12 from being made. But the normal function—or functions—of ABHD12, and the precise reasons its absence causes disease, have been unclear.

The Cravatt laboratory, in a 2013 study, engineered "knockout" mice that lack the ABHD12 gene, and determined that the ABHD12 protein is an enzyme that normally breaks down lysophospholipids—fat-related molecules that include lyso-PS, an important stimulator of immune activity. In the new study, Cravatt's team collaborated with researchers at Abide Therapeutics to extend their work on ABHD12 by developing a compound that selectively inhibits the enzyme's function.

"The idea was to use this inhibitor to disrupt ABHD12 in otherwise normal adult mice, and compare the effects to what we see in the ABHD12-knockout mice that never have a working copy of the enzyme," Cravatt says.

The team found that in adult mice, reducing ABHD12 activity with the inhibitor led to a rise in lyso-PS in immune cells called macrophages, as well as in brain tissue. The rise wasn't as great as that seen in the ABHD12-knockout mice, and even four weeks of treatment with the inhibitor appeared to cause only slight hearing defects—nothing like the profound defects experienced by PHARC patients. However, in further experiments conducted by the laboratory of study co-senior author John Teijaro, an assistant professor in the Department of Immunology and Microbiology at Scripps Research, it was clear that the reduction in ABHD12 activity had a big effect on the mouse immune system.

Teijaro's team infected the inhibitor-treated mice with a virus called lymphocytic choriomeningitis virus (LCMV) clone 13, which can deactivate elements of the immune system to establish a persistent infection in its hosts. Ordinary mice infected with LCMV clone 13 typically have minor symptoms but take a long time to clear the infection.

Teijaro and colleagues found that the ABHD12-knockout mice, as well as the mice treated with the ABHD12 inhibitor, had immune responses that were much more vigorous and effective in clearing the virus, often excessively so.

"The enhanced mortality and lung pathology were striking in clone-13 infected mice following ABHD12 inhibition or deletion," Teijaro says.

The findings suggest several possibilities to investigate with future research. For example, the enhanced immune activity in the knockout and inhibitor-treated mice hints that the signs and symptoms of PHARC may have an immunological basis.

"It is now known that the immune system plays a big role in many brain diseases, including neurodegenerative diseases such as Alzheimer's and Parkinson's," Cravatt notes. "There have also been hints of immune involvement in developmental brain disorders such as autism and schizophrenia."

He adds that if PHARC turns out to be caused in part by chronic brain and nerve inflammation, it might be treatable, if caught early enough, with anti-inflammatory or immune-suppressing drugs.

At the same time, treatments that target ABHD12, reducing its activity and stimulating the immune system, might have even broader use.

"The enhanced killer-T-cell activity we saw following ABHD12 deletion in the LCMV-infected mice suggests that blocking ABHD12 may enhance T-cell responses in immune suppressive environments such as chronic viral infections and cancers," Teijaro says.

"We're certainly eager to explore those possibilities," Cravatt says.

More information: Daisuke Ogasawara et al, Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo, Nature Chemical Biology(2018).  DOI: 10.1038/s41589-018-0155-8

Journal reference: Nature Chemical Biology 

Provided by: The Scripps Research Institute

https://medicalxpress.com/news/2018-11-trail-rare-genetic-disease-scientists.html

Biologists discover an unusual hallmark of aging in neurons

November 27, 2018, Massachusetts Institute of Technology

Neurons from 19-month-old mice (bottom row) show much higher rates of oxidative stress than neurons from 9-week-old mice (top row). Lipofuscin, a molecule associated with aging-related oxidative stress, appears red. Credit: Hyeseung Lee

As we age, neurons in our brains can become damaged by free radicals. MIT biologists have now discovered that this type of damage, known as oxidative stress, produces an unusual pileup of short snippets of RNA in some neurons.

This RNA buildup, which the researchers believe may be a marker of neurodegenerative diseases, can reduce protein production. The researchers observed this phenomenon in both mouse and human brains, especially in a part of the brain called the striatum—a site involved in diseases such as Parkinson's and Huntington's.

"The brain is very metabolically active, and over time, that causes oxidative damage, but it affects some neurons more than others," says Christopher Burge, an MIT professor of biology. "This phenomenon appears to be a previously unrecognized consequence of oxidative stress, which impacts hundreds of genes and may influence translation and RNA regulation globally."

Burge and Myriam Heiman, the Latham Family Career Development Associate Professor of Brain and Cognitive Sciences, are the senior authors of the paper, which appears in the Nov. 27 issue of Cell Reports. Peter Sudmant, a former MIT postdoc, is the lead author of the paper, and postdoc Hyeseung Lee and former postdoc Daniel Dominguez are also authors.

A mysterious finding

For this study, the researchers used a technique developed by Heiman that allows them to isolate and sequence messenger RNA from specific types of cells. Messenger RNA carries protein-building instructions to cell organelles called ribosomes, which read the mRNA and translate the instructions into proteins by stringing together amino acids in the correct sequence.

Heiman's technique involves tagging ribosomes from a specific type of cells with green fluorescent protein, so that when a tissue sample is analyzed, researchers can use the fluorescent tag to isolate and sequence RNA from only those cells. This allows them to determine which proteins are being produced by different types of cells.

"This is particularly useful in the nervous system where you've got different types of neurons and glia closely intertwined together, if you want to isolate the mRNAs from one particular cell type," Burge says.

In separate groups of mice, the researchers tagged ribosomes from either D1 or D2 spiny projection neurons, which make up 95 percent of the neurons found in the striatum. They labeled these cells in younger mice (6 weeks old) and 2-year-old mice, which are roughly equivalent to humans in their 70s or 80s.

The researchers had planned to look for gene expression differences between those two cell types, and to explore how they were affected by age. "These two types of neurons are implicated in several neurodegenerative diseases that are aging-related, so it is important to understand how normal aging changes their cellular and molecular properties," Heiman says.

To the researchers' surprise, a mysterious result emerged—in D1 neurons from aged mice (but not neurons from young mice or D2 neurons from aged mice), they found hundreds of genes that expressed only a short fragment of the original mRNA sequence. These snippets, known as 3' untranslated regions (UTRs), were stuck to ribosomes, preventing the ribosomes from assembling normal proteins. "While these RNAs have been observed before, the magnitude and age-associated cell-type specificity was really unprecedented," says Sudmant.

The 3' UTR snippets appeared to originate from about 400 genes with a wide variety of functions. Meanwhile, many other genes were totally unaffected.

"There are some genes that are completely normal, even in aged D1 neurons. There's a gene-specific aspect to this phenomenon that is quite interesting and mysterious," Burge says.

The findings led the researchers to explore a possible role for oxidative stress in this 3' UTR accumulation. Neurons burn a great deal of energy, which can produce free radicals as byproducts. Unlike many other cell types, neurons do not get replaced, so they are believed to be susceptible to accumulated damage from these radicals over time.

The MIT team found that the activation of oxidative stress response pathways was higher in D1 neurons compared to D2 neurons, suggesting that they are indeed undergoing more oxidative damage. The researchers propose a model for the production of isolated 3' UTRs involving an enzyme called ABCE1, which normally separates ribosomes from mRNA after translation is finished. This enzyme contains iron-sulfur clusters that can be damaged by free radicals, making it less effective at removing ribosomes, which then get stuck on the mRNA. This leads to cleavage of the RNA by a mechanism that operates upstream of stalled ribosomes.

"Sending neural signals takes a lot of energy," Burge says. "Over time, that causes oxidative damage, and in our model one of the proteins that eventually gets damaged is ABCE1, and that triggers the production of 3' UTRs."

RNA buildup

The researchers also found the same accumulation in most parts of the human brain, including the frontal cortex, which is very metabolically active. They did not see it in most other types of human tissue, with the exception of liver tissue, which is exposed to high levels of potentially toxic molecules.

In human brain tissue, the researchers found that the amount of 3' UTRs gradually increased with age, which fits their proposed model of gradual damage by oxidative stress. The researchers' findings and model suggest that the production of these 3' UTRs involves the destruction of normal mRNAs, reducing the amount of protein produced from the affected genes. This buildup of 3' UTRs with ribosomes stuck to them can also block ribosomes from producing other proteins.

It remains to be seen exactly what effect this would have on those neurons, Burge says, but it is possible that this kind of cellular damage could combine with genetic and environmental factors to produce a general decline in cognitive ability or even neurodegenerative conditions such as Parkinson's disease. In future studies, the researchers hope to further explore the causes and consequences of the accumulation of 3' UTRs.

Journal reference: Cell Reports 

Provided by: Massachusetts Institute of Technology

https://medicalxpress.com/news/2018-11-biologists-unusual-hallmark-aging-neurons.html

Can learning music deter dementia?

 November 27, 2018, Massey University

PhD psychology researcher Ryan Sutcliffe with the tools for his study - a guitar and non-invasive brain imaging technology. Credit: Massey University


Ryan Sutcliffe loves to play the guitar, and writes and performs his own songs. Now, the doctoral psychology researcher has a dream project combining his musical and academic interests in a study to test whether music lessons can help maintain brain health in ageing.

Mr Sutcliffe is seeking 60 people aged over 60 years in the Manawatū region to take part in a study to determine if learning a musical instrument in later life can affect cognition, and act as a way of slowing the inevitable decline in brain function and, perhaps, even defer the onset of dementia.

He will be offering free guitar lessons and a free guitar to 30 people randomly assigned to one group. The other 30 in the control group will take part in a musicclub involving listening to and discussing a wide variety of music, sharing favourite music and doing music quizzes. 

"What I'm interested in is how we can use music in successful brain ageing," says Mr Sutcliffe, who is based in the School of Psychology at Massey University. "The rationale for this study is that by learning a musical instrument, we can reduce chances of having further brain degeneration than already might occur in healthy ageing."

How does strumming lead to successful brain ageing? "When you're learning an instrument, it's the motor aspects [using your hands], it's the listening aspect, it's the visual aspect, and also the concentration. When you tie all of these things together, you're actually really exercising your brain, which is important for the maintenance of healthy brain function." 

Pleasure also has a cognitive impact through feeling rewarded by making progress in learning how to make music. The idea is that music tuition could be an early stage intervention to bolster the brain's inherent neuroplasticity.

Novel study

As far as he's aware, this is the first study anywhere to teach music to an older group of participants and to record brain activity. 

Both groups will undergo a non-invasive neurological session before and after the music lessons or club activities. During those tasks he will record brain activity, using an imaging method called functional near-infrared spectroscopy (fNIRS). 

"In this session, people will be asked to label the emotion in music clips and faces, and complete some questions tapping into verbal and non-verbal reasoning while wearing a head cap which uses light to measure blood flow throughout the brainsurface," he says. The session will last roughly one and a half hours.

Ryan Sutcliffe testing the brain imaging technology to be used in his research with his co-supervisor Dr Ute Kreplin. Credit: Massey University

Prospective participants must be free of any history of head injury, stroke or other neurological impacts (including neurodegenerative conditions such as Parkinson's and Alzheimer's disease). Depending on which group participants are assigned to, they will receive either a new guitar to keep, or a gift card of equivalent value. Participants must not currently play an instrument, currently consider themselves a musician, or have had more than three years of earlier music training (including self-teaching, formal lessons, or otherwise).

Those who agree to take part in this project will first be asked to complete an online questionnaire to collect demographic information. Following this, participants will be asked to attend one of two weekly groups – either the music appreciation and discussion club or the guitar learning programme. "These lessons will provide participants with a basic introduction to contemporary guitar playing, with an emphasis on song-learning and performance, as opposed to music theory," he says.

Music tuition – a gamechanger in ageing health care? 

"The most valuable outcome of the proposed research would be that late-life music learning prevents declines in brain health and consequently, cognitive, mental, and social abilities. Learning a musical instrument could therefore be a simple, inexpensive, and non-invasive method for reducing older adults' likelihood of developing age-based neurodegenerative diseases," Mr Sutcliffe says. 

"Group music lessons could be implemented in rest homes and community groups, with the goal of easing the societal pressure associated with increasing aged populations."

Mr Sutcliffe knows the power of music since he picked up guitar at age nine. He took lessons and has played and written songs ever since, including in a high school jazz group and more recently, a gig in Palmerston North. 

"Because music is a big part of my life and I listen to music all the time, I've always been interested in the psychological side of it. It's really cool that I've been able to incorporate playing the guitar into a Ph.D. in psychology."

He is currently seeking volunteers for this project and encourages anyone interested to contact him for more information or to register for the study: E: rsutcliffe14@gmail.com or M: 027 267 1235

Mr Sutcliffe hopes to start the groups, which will run for four months, in February and March 2019.

Provided by: Massey University 

https://medicalxpress.com/news/2018-11-music-deter-dementia.html

Microglia react distinctively during inflammation

 November 27, 2018, Luxembourg Institute of Health

Confocal picture of microglia stained with macrophage-specific marker (IBA) shown in yellow. Cell nuclei are shown in pink (Hoechst). Credit: LIH

The NorLux Neuro-Oncology Laboratory at LIH's Department of Oncology conducts research on brain diseases, with a special emphasis on glioma biology, drug resistance and systems approaches. Within this research unit, Dr. Alessandro Michelucci focuses on the role of glial cells and inflammatory responses. Jointly with team member Dr. Carole Sousa and collaborating research groups from LIH and the University of Luxembourg, the team published their findings in the November 2018 issue of EMBO Reportsin an article titled "Single-cell transcriptomics reveals distinct inflammation-induced microglia signatures."

Studying the effect of inflammation 

The brain is a unique organ with its own tailored immune cells and mechanisms, distinct from those of the rest of the body. The central nervous system (CNS) contains specialized parenchymal-resident phagocytes, microglia, that survey and modulate the neural environment and respond to infections, toxins or contaminants, thereby promoting neuronal health and ensuring normal brain function. Microglia can sense homeostatic perturbations and coordinate immune responses between the periphery and the CNS. Dysfunctional microglia have been observed in chronic neurological disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and brain cancer, and are thought to worsen their outcome.

The activity of microglia during acute neuro-inflammatory processes as those caused by infection remains largely elusive. Acute inflammation represents the early phase of what could result in chronic inflammation and/or neurodegenerative processes. Therefore, microglial responses at this very early phase of perturbation should provide important insights into the cells' role and adaptive capacities. The aim of the present study was to uncover the heterogeneity of microglial responses under early acute inflammatory conditions to elucidate potential beneficial signatures of subpopulations that could contribute to resolving inflammation and avoiding to enter into a chronic phase causing disease.

To study the cells' activation, the researchers from LIH isolated microglia from mice injected with lipopolysaccharide (LPS), a bacterial component mimicking an acute infection and triggering inflammation signals in the brain. The use of this model combined with modern single-cell sequencing and multicolor flow cytometry allowed for an in-depth profiling of microglia activation at the transcriptomics level.

Distinct inflammation-induced signatures revealed

The researchers observed a marked global downregulation of the typical microglial homeostatic signature and simultaneously an up-regulation of genes classically activated by inflammation. "When investigating further and comparing to published data, we could show that under acute systemic inflammation, microglia presented a highly activated state that is clearly distinct from neurodegenerative disease-associated profiles," says Dr. Sousa, who performed most of the experimental work.

Importantly, the researchers also noticed unforeseen heterogeneity among the activated cells. They hypothesized that a subset of reactive microglia may be less sensitive to the inflammatory stimulus caused by LPS or partly recovered from the activated state.

"Our findings reveal that microglia responses in inflammatory conditions are heterogeneous and clearly distinct from the responses described in the context of neurodegenerative diseases," says Dr. Michelucci, who initiated and led the project. "We hope that these results obtained from single-cell transcriptomic profiling of microglia under inflammatory conditions will contribute to the establishment of new resources that will clarify the specific responses to brain disorders. This should boost the development of novel therapeutic strategies against CNS diseases with an immunological component."

More information: Carole Sousa et al, Single‐cell transcriptomics reveals distinct inflammation‐induced microglia signatures, EMBO reports (2018).  DOI: 10.15252/embr.201846171

Journal reference: EMBO Reports

Provided by: Luxembourg Institute of Health

https://medicalxpress.com/news/2018-11-microglia-react-distinctively-inflammation.html

Can Immunotherapy Offer New Hope for Parkinson’s Sufferers?

David Cox is a science and health writer based in the UK.

November 26, 2018

Parkinson’s disease affects many people around the world, but effective treatments are proving elusive. Immunotherapy is being developed as a new treatment for the disease. I spoke to some experts in the field to find out just how promising the new therapies being developed are.

More than 10 million people worldwide are currently living with Parkinson’s disease, an incurable neurodegenerative disorder. Current Parkinson’s treatments are limited as they only attempt to mask the symptoms of the disease rather than dealing with its cause. But there is potential hope on the horizon.

Biotech companies across Europe and the US are now developing a range of immunotherapies which attempt to slow down or even completely halt the progression of Parkinson’s.

This may be possible because over the past two decades, scientists have developed a concrete hypothesis for how Parkinson’s develops and spreads. They believe the main culprit is a toxic form of a protein called alpha synuclein which begins to accumulate in the brain over time due to mutations in the gene that encodes the protein. As clusters of alpha synuclein form inside the cells, they cause the characteristic Parkinson’s symptoms ranging from tremors to muscle stiffness. The increasing toxicity leads to neuronal degeneration and ultimately cell death.

As a result, over the past ten years, biotechs have been designing ways of using antibodies to specifically target and bind to the toxic form of alpha synuclein and remove it from the body.

“The belief is that if you can you can reduce the levels of this toxic species, you can slow down the progression of the disease,” Gunilla Osswald, CEO of Stockholm-based BioArctic, told me. “This is what we’ve seen in preclinical models using mice. Our antibody makes the motor symptoms come much later, and they survive far longer.”

Most of these immunotherapies are currently in early stage clinical trials. But while they all utilize antibodies, they use two main approaches. One of the key questions over the next few years is to see which approach is most effective.

Artificial antibodies to target toxic alpha synuclein

The strategy being applied by the majority of biotechs involves regular intravenous injections of artificially generated antibodies, and is known as passive immunotherapy.

“The advantage of using artificially generated antibodies is that it gives us full control of the dosage and exactly where the antibody binds,” said Wagner Zago, CSO of Prothena, which has its headquarters in Dublin. “We’ve learnt that to drive efficacy, it’s really important for the antibody to have a very high binding affinity with alpha synuclein. It also makes trial design more straightforward as you can ensure that every patient has the same exposure.”

Alpha synuclein protein

Prothena has developed an antibody to target the toxic form of alpha synuclein, and is conducting trials with the pharmaceutical company Roche. In an initial Phase I trial of 80 Parkinson’s patients, the antibody was capable of crossing the blood brain barrier and rapidly reducing the levels of toxic alpha synuclein in the brain.

“One of the key aspects of our approach is that our antibody does not just neutralise these forms of alpha synuclein after it binds to them, but it also helps… the brain clear it very quickly,” noted Zago. “This clearance is a very important mechanism.”

The question now is whether clearing alpha synuclein stabilizes or improves symptoms in Parkinson’s patients over a prolonged period of time. This has yet to be proven, but Prothena are set to find out first. While most other companies developing passive immunotherapies are still in the preparation stages for Phase I or II trials, Prothena’s therapy is currently being assessed in a Phase II trial of 300 patients in the early stages of Parkinson’s disease with the results expected in 2020.

The home-grown antibody approach

Vienna-based AFFiRiS is also attempting to reduce the levels of toxic alpha synuclein through a an antibody response. Its method, known as active immunotherapy, involves injecting a synthetically engineered protein fragment that mimics the toxic form of alpha synuclein. This induces the body to produce its own antibodies, which will bind to and remove toxic alpha synuclein molecules from the brain.

While passive immunotherapy would need to be applied in regular weekly or monthly infusions, active immunotherapy has the potential to have long-lasting effects, possibly only requiring yearly injections.

We don’t get the same concentrations of antibodies with our approach compared to passive immunotherapy,” explained Gunther Staffler, CTO of AFFiRiS. He pointed out that, while passive approaches can result in the body creating antibodies against the drug, making it ineffective, that is not an issue with active immunotherapy.

So far, AFFiRiS has completed a Phase Ib trial, observing 32 Parkinson’s patients over the course of four years. The early results are promising. The therapy reduced levels of toxic alpha synuclein in the central nervous system and showed signs of stabilizing some of the symptoms of the disease such as tremors and problems with physical movement. AFFiRiS is now preparing a Phase II trial of 300 or more patients, to begin in 2020, which aims to validate and explore their findings further

Key questions remain

There are a number of key questions which will only begin to be answered over the next five years as the results return from Phase II trials. We still don’t know whether reducing levels of toxic alpha synuclein will stabilize or improve symptoms in a large number of Parkinson’s patients over a prolonged period of time. Staffler cautions that it may still turn out that scientists have been chasing the wrong drug target all along, as seems to be the case with Alzheimer’s disease and amyloid beta“The alpha synuclein theory of Parkinson’s is still just a hypothesis,” Staffler says. “But we are now on the cusp of either falsifying or validating that hypothesis.”

Even if the new immunotherapies do eventually make it all the way to market, it will be far from a complete cure for Parkinson’s. But they do offer the potential to perhaps halt the disease in its tracks, which would be life-changing for the millions of patients affected.

“Finding a complete cure will take a long time,” says Osswald. “But these disease-modifying treatments in development right now could be a huge step forward, adding to the symptomatic treatments on the market, which are good to some extent, but have some other difficulties. I think Parkinson’s is really an area where we will see things evolving in the future, more and more.”

https://labiotech.eu/features/immunotherapy-parkinsons-disease/