Posts tagged neurodegenerative diseases

Recycling is not only good for the environment, it’s good for the brain. A study using rat cells indicates that quickly clearing out defective proteins in the brain may prevent loss of brain cells.

Results of a study in Nature Chemical Biology suggest that the speed at which damaged proteins are cleared from neurons may affect cell survival and may explain why some cells are targeted for death in neurodegenerative disorders. The research was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

One of the mysteries surrounding neurodegenerative diseases is why some nerve cells are marked for destruction whereas their neighbors are spared. It is especially puzzling because the protein thought to be responsible for cell death is found throughout the brain in many of these diseases, yet only certain brain areas or cell types are affected.

In Huntington’s disease and many other neurodegenerative disorders, proteins that are misfolded (have abnormal shapes), accumulate inside and around neurons and are thought to damage and kill nearby brain cells. Normally, cells sense the presence of malformed proteins and clear them away before they do any damage. This is regulated by a process called proteostasis, which the cell uses to control protein levels and quality.

In the study, Andrey S. Tsvetkov and his colleagues from the University of California, San Francisco (UCSF) and Duke University, Durham, N.C., showed that differences in the rate of proteostasis may be the clue to understanding why certain nerve cells die in Huntington’s, a genetic brain disorder that leads to uncontrolled movements and death.

To measure how quickly proteins are cleared away from cells, the researchers developed a new technique called optical pulse-labeling, allowing them to follow specific proteins in individual living cells. To test the technique, they grew brain cells in a dish and turned on Dendra2, a photoswitchable protein that glows from green to red after being hit by a specific type of light. Both the red and green glow can be followed until the protein is cleared from the cell. In this way, the researchers could track the lifetime of newly produced Dendra2 (which glows green) and older, photoswitched Dendra2 (which glows red) until the protein was cleared away from the cell.

"Before this new technique, there was no way to look at individual neurons and their capacity to handle proteins. This method provides a real-time readout of how fast proteins are turned over in neurons and gives us a look at some of the mechanisms involved," said Margaret Sutherland, Ph.D., program director at NINDS.

The researchers followed Dendra2 in a set of striatal neurons, which they obtained from rats. The striatum (where striatal neurons are located) is a brain region involved in a number of brain functions including planning movements and is most heavily affected in Huntington’s disease. They discovered that the mean lifetime of the protein (how long it remained in the cell) varied three- to fourfold, suggesting that rates of proteostasis were different among individual neurons. In other words, some cells may process an identical protein much slower than others.

Then, the researchers investigated how cells deal with different forms of huntingtin, the protein involved in Huntington’s. They fused Dendra2 on the end of a normal or mutant version of huntingtin to track how long the protein remained in cells. The mutant version of huntingtin is longer, and contains three building blocks of the protein repeated an abnormal number of times. These repeats in huntingtin are what cause it to misfold, eventually leading to neuron death and the symptoms of the disease. As predicted, in their experiments, the mutant form of huntingtin caused more rat cells to die than did the normal form of the protein.

The researchers found that the amount of time the mutant protein remained in the cell predicted neuronal survival: shorter mean lifetimes of mutant huntingtin were associated with longer neuronal survival. A shorter mean lifetime indicates that a protein does not remain in the cell for a long time, and that proteostasis is working effectively to clear it away. This suggests that improving proteostasis in Huntington’s brains may improve neuronal survival.

To test this idea, the researchers activated Nrf2, a protein known to regulate protein processing. When Nrf2 was turned on, the mean lifetime of huntingtin was shortened, and the neuron lived longer.

"Nrf2 seems like a potentially exciting therapeutic target. It is profoundly neuroprotective in our Huntington’s model and it accelerates the clearance of mutant huntingtin," said Dr. Steven Finkbeiner, senior author of the paper.

Although both striatal and cortical neurons are affected by mutant huntingtin, striatal neurons are more susceptible to cell death. The investigators found that striatal neurons were not as effective as cortical neurons in recognizing and clearing away the mutant protein.

"One surprising finding from these experiments was the significance of single cells’ ability to clear mutant huntingtin. It turned out that this ability largely predicted their susceptibility, whether that neuron came from the most vulnerable region of the brain – the striatum, or the cortex, which is less vulnerable," said Dr. Finkbeiner. The findings indicate that the toxicity of the damaged proteins may cause neurodegeneration by interfering with the proteostasis system, affecting how quickly they are cleared from neurons.

"The results should remind us that focusing on the disease-causing proteins is only one side of the coin. To understand why some cells die and others are spared, we may need to recognize that there are major, largely unrecognized cell-specific differences in the ways that various types of neurons recognize and dispose of disease-causing proteins," continued Dr. Finkbeiner.

The researchers explored potential mechanisms behind differences in proteostasis. One way that cells normally get rid of proteins is through autophagy — a process in which proteins are packed up into spheres and then broken down. Results in this paper suggested that neurons increased the rate of autophagy when they sensed that the mutant form of huntingtin was accumulating, indicating the autophagy system may be a drug target.

"These findings provide evidence that our brains have powerful coping mechanisms to deal with disease-causing proteins. The fact that some of these diseases don’t cause symptoms we can detect until the fourth or fifth decade of life, even when the gene has been present since birth, suggests that those mechanisms are pretty good," said Dr. Finkbeiner.

Future research is needed to determine why coping mechanisms fail as brain cells age and how neurons in the healthy brain keep the proteostasis system functioning.

"New research methods that help us understand how individual neurons function will increase our understanding of central nervous system disorders and help identify new treatments. It is critical to continue working on the methods such as those described in this paper," said Dr. Sutherland.

(Source: eurekalert.org)

The development of new drugs for improving treatment of Alzheimer’s and Parkinson’s disease is a step closer after recent research into how stem cells migrate and form circuits in the brain.

The results from a study by researchers at The University of Auckland’s Centre for Brain Research may hold important clues into why there is less plasticity in brains affected by Parkinson’s and Alzheimer’s disease, and links to insulin resistance and diabetes.

The major five-year project to understand how stem cells start and stop migrating in the brain has also helped to unlock the secrets of how stem cells migrate during development and in adulthood.

The study revealed new information on how connectivity between brain cells is improved or worsened, says senior study author, Dr Maurice Curtis who conceived and directed the research. The experiments were carried out at the Centre for Brain Research laboratories by Dr Hector Monzo. Collaborators included a director of the CBR, Distinguished Professor Richard Faull, Dr Thomas Park, Dr Birger Dieriks, Deidre Jansson and Professor Mike Dragunow.

“We have begun testing new novel drug compounds that target how polysialic acid is removed from the cell in the hope of improving neuron connectivity,” says Dr Curtis.

He explains that stem cells in the brain are immature brain cells that must migrate from their birthplace to a position in the brain where they will connect with other brain cells, turn into adult brain cells (neurons) and become part of the brain’s circuitry.

“Even once the neuron has found its location, the neuron’s tentacles (or dendrites) need to forage to find other neurons to connect with to form circuits. This would be easy except that in the adult brain the cells are surrounded by a fairly rigid matrix (extracellular matrix) and so migration or foraging becomes almost impossible in this high friction environment.”

“The way the cell overcomes this ‘friction’ is by placing large amounts of a special slippery molecule called ‘polysialic acid-neural cell adhesion molecule’ onto the cell surface,” says Dr Curtis. “This allows the cell to migrate or forage with only a fraction of the friction it once had and this also reduces the energy requirements of the cell.”

Once the cell has migrated to its destination, the slippery coating is removed and the cell becomes locked in place ready to connect with other cells. In the case of the dendritic foraging, the polysialic acid must be removed in order for the dendrite to connect with another cell (synapse formation).

“We have known for at least 20 years that this process occurs but despite extensive studies by a number of groups internationally we have been in the dark about what controls this process,” he says. “Studies in my laboratory have demonstrated what happens to the slippery molecules once the cell no longer needs them.”

There were three possibilities for this process:

• that enzymes cut them off the outside of the cell
• that the friction wears it off the cell or
• the cell internalises the slippery substance and recycles it ready for future use.

“For the past five years, we have systematically studied how this process is controlled,” says Dr Curtis. “Our findings have demonstrated that cells internalise the slippery molecule after receiving two specific cues.”

One of these cues is from collagen which makes up part of the rigid structure outside of the cell and the other is from a gaseous molecule called nitric oxide which triggers the outer membrane of the cell to internalise the slippery molecules.

“What we also discovered is that when there is an increased amount of insulin and insulin-like growth factor 1 (which has some similar functions to insulin) present in the culture, the cell cannot internalise the slippery molecules and instead they remain on the cell surface.”

“The key to the breakthrough was in determining that the process by which the polysialic acid is added to the cell surface was so persistent that it needed to be stopped in order to study how the polysialic acid was removed,” says Dr Curtis. “This required extensive trialling of many different cell growth conditions, enzyme concentrations and growing the cells in many different extracellular matrices.”

This is interesting because it is well known that in Parkinson’s disease and Alzheimer’s disease the brain is less sensitive to insulin, he says.

“In our studies in cells the insulin blocks the removal of polysialic acid and therefore the cell cannot connect properly and form synapses with other nearby cells.”

“This may hold major clues to why there is less plasticity in brains affected by Parkinson’s and Alzheimer’s disease in adults as well as helping to unlock the secrets of how stem cells migrate during development of the brain”, says Dr Curtis.

The Gus Fisher Postdoctoral Fellowship, the Auckland Medical Research Foundation and the Manchester Trust were the main sponsors of this research work.

The study results were published online this month in an ‘ahead of print’ version of The Journal of Neurochemistry.

(Source: auckland.ac.nz)

Clinical trials of drug treatments for neurological diseases such as Alzheimer’s and Parkinson’s often fail because the animal studies that preceded them were poorly designed or biased in their interpretation, according to a new study from an international team of researchers. More stringent requirements are needed to assess the significance of animal studies before testing the treatments in human patients, the researchers say.

The team — led by John Ioannidis, MD, DSc, a professor of medicine at the Stanford University School of Medicine and an expert in clinical trial design — assessed the results of more than 4,000 animal studies in 160 meta-analyses of potential treatments for neurological disorders from Alzheimer’s disease, Parkinson’s disease, stroke, spinal-cord injury and a form of multiple sclerosis. (A meta-analysis is a study that compiles and assesses information and conclusions from many independent experiments of a treatment, or intervention, for a particular condition.).

They determined that only eight of the 160 studies of potential treatments yielded the statistically significant, unbiased data necessary to support advancing the treatment to clinical trials. In contrast, 108 of the treatments were deemed at least somewhat effective at the time they were published.

Ioannidis and his collaborators at the University of Edinburgh in Scotland and the University of Ioannina School of Medicine in Greece say that animal studies of potential interventions can be made more efficient and reliable by increasing average sample size, being aware of statistical bias, publishing negative results and making all the results of all experiments on the effectiveness of a particular treatment — regardless of their outcome — freely accessible to scientists.

"Some researchers have postulated that animals may not be good models for human diseases," said Ioannidis. "I don’t agree. I think animal studies can be useful and perfectly fine. The problem is more likely to be related to the selective availability of information about the studies conducted on animals." Although the researchers focused here on neurological disorders, they believe it is likely that similar bias exists in animal studies of other types of disorders.

Ioannidis, who directs the Stanford Prevention Research Center, is the senior author of the research, published online in PLoS Biology on July 16. Lecturer Konstantinos Tsilidis, PhD, and postgraduate fellow Orestis Panagiotou, MD, of the University of Ioannina share lead authorship of the study. Panagiotou is currently a researcher at the National Cancer Institute’s Division of Cancer Epidemiology and Genetics.

Ioannidis is known for his efforts to strengthen the way that research is planned, carried out and reported. He was called “one of the world’s foremost experts on the credibility of medical research” in a profile published in The Atlantic magazine in 2010. He outlined some of the problems he observed in a 2005 essay in PLoS-Medicine titled, “Why most published research findings are false.” The essay is one of the most-downloaded articles in the history of the Public Library of Science, according to the journal’s media relations office.

For the new study, Ioannidis and his colleagues evaluated results in a database of the thousands of animal studies compiled over the years through the CAMARADES initiative (Collaborative Approach to Meta-Analysis and Review of Animal Data in Experimental Studies), led by professor Malcolm MacLeod, PhD, from the University of Edinburgh, who is also a co-author of the study.

The team compared the number of experiments in the meta-analyses that would have been expected to yield positive results (based on their predicted statistical power) with the actual number of experiments with published positive results. The difference was striking: 919 expected versus the 1,719 that were published, implying that either negative results were not published, or that the results of the experiments were interpreted too optimistically.

"We saw that it was very common for these interventions to have published evidence that they would work," said Ioannidis. "It was extremely common to have results that suggest they would be effective in humans."

Furthermore, nearly half (46 percent) of the 160 meta-analyses showed evidence of small-study effects — a term used to describe the fact that a small study using fewer numbers of animals is more likely to find the intervention more effective than a larger study with many animals.

Ioannidis speculated that a reluctance to publish negative findings (that is, those that conclude that a particular intervention did not work any better than the control treatment) and a perhaps unconscious desire on the part of researchers to find a promising treatment has colored the field of neurological research. Obscuring access to studies that conclude a particular treatment is ineffective, while also publishing positive results that are likely to be statistically flawed, tilts the perception toward the potential effectiveness of an intervention and encourages unwarranted human clinical trials.

"There are no standard rules that guide a decision to move from animal studies into human clinical trials," said Ioannidis, who also holds C.F. Rehnborg Professorship at Stanford. "Sometimes interventions are tested in humans with very little evidence that they may be effective. Of the 160 analyses we studied, only eight had what we would call strong evidence of potential effectiveness with no hint of bias in the preliminary animal studies. And of these eight, only two have given positive results in humans."

Ioannidis believes the development of consortiums of groups of researchers studying a particular intervention, coupled with the free sharing of all data about its effectiveness, or lack thereof, is a good first step in reducing bias in animal studies.

"Under the current conditions, only a tiny proportion of interventions that have published some promising results in animals have shown to be at all effective in humans. For example, while dozens of treatments on ischemic or hemorrhagic stroke seem to work in the animal literature, almost none of them have worked in humans," said Ioannidis. "It is hard to believe we could not improve upon that translation record. If we raise the bar for moving into human trials, centralize researchers’ efforts and make all results available, it will be much easier for researchers to know whether they have a potential winner, and it would increase the efficiency of human clinical trials enormously."

(Source: med.stanford.edu)

Amyotrophic Lateral Sclerosis (ALS) is a devastating motor neuron disease that rapidly atrophies the muscles, leading to complete paralysis. Despite its high profile — established when it afflicted the New York Yankees’ Lou Gehrig — ALS remains a disease that scientists are unable to predict, prevent, or cure.

Although several genetic ALS mutations have been identified, they only apply to a small number of cases. The ongoing challenge is to identify the mechanisms behind the non-genetic form of the disease and draw useful comparisons with the genetic forms.

Now, using samples of stem cells derived from the bone marrow of non-genetic ALS patients, Prof. Miguel Weil of Tel Aviv University’s Laboratory for Neurodegenerative Diseases and Personalized Medicine in the Department of Cell Research and Immunology and his team of researchers have uncovered four different biomarkers that characterize the non-genetic form of the disease. Each sample shows similar biological abnormalities to four specific genes, and further research could reveal additional commonalities. “Because these genes and their functions are already known, they give us a specific direction for research into non-genetic ALS diagnostics and therapeutics,” Prof. Weil says. His initial findings were reported in the journal Disease Markers.

Giving in to stress

To hunt for these biomarkers, Prof. Weil and his colleagues turned to samples of bone marrow collected from ALS patients. Though more difficult to collect than blood, bone marrow’s stem cells are easy to isolate and grow in a consistent manner. In the lab, he used these cells as cellular models for the disease. He ultimately discovered that cells from different ALS patients shared the same abnormal characteristics of four different genes that may act as biomarkers of the disease. And because the characteristics appear in tissues that are related to ALS — including in muscle, brain, and spinal cord tissues in mouse models of genetic ALS — they may well be connected to the degenerative process of the disease in humans, he believes.

Searching for the biological significance of these abnormalities, Prof. Weil put the cells under stress, applying toxins to induce the cells’ defense mechanisms. Healthy cells will try to fight off threats and often prove quite resilient, but ALS cells were found to be overwhelmingly sensitive to stress, with the vast majority choosing to die rather than fight. Because this is such an ingrained response, it can be used as a feature for drug screening for the disease, he adds.

The hunt for therapeutics

Whether these biomarkers are a cause or consequence of ALS is still unknown. However, this finding remains an important step towards uncovering the mechanisms of the disease. Because these genes have already been identified, it gives scientists a clear direction for future research. In addition, these biomarkers could lead to earlier and more accurate diagnostics.

Next, Prof. Weil plans to use his lab’s high-throughput screening facility — which can test thousands of compounds’ effects on diseased cells every day — to search for drug candidates with the potential to affect the abnormal expression of these genes or the stress response of ALS cells. A compound that has an impact on these indicators of ALS could be meaningful for treating the disease, he says.

Prof. Weil is the director of the new Cell Screening Facility for Personalized Medicine at TAU. The facility is dedicated to finding potential drugs for rare and Jewish hereditary diseases.

(Source: aftau.org)

(Source: sri.com)

Neurodegenerative diseases are not all alike. Two individuals suffering from the same disease may experience very different age of onset, symptoms, severity, and constellation of impairments, as well as different rates of disease progression. Researchers in the Perelman School of Medicine at the University of Pennsylvania have shown one disease protein can morph into different strains and promote misfolding of other disease proteins commonly found in Alzheimer’s, Parkinson’s and other related neurodegenerative diseases.

Virginia M.Y. Lee, PhD, MBA, professor of Pathology and Laboratory Medicine and director of the Center for Neurodegenerative Disease Research, with co-director, John Q. Trojanowski MD, PhD, postdoctoral fellow Jing L. Guo, PhD, and colleagues, discovered that alpha-synuclein, a protein that forms sticky clumps in the neurons of Parkinson’s disease patients, can exist in at least two different structural shapes, or “strains,” when it clumps into fibrils, despite having precisely the same chemical composition.

These two strains differ in their ability to promote fibril formation of normal alpha-synuclein, as well as the protein tau, which forms neurofibrillary tangles in individuals with Alzheimer’s disease.

Importantly, these alpha-synuclein strains are not static; they somehow evolve, such that fibrils that initially cannot promote tau tangles acquire that ability after multiple rounds of “seeded” fibril formation in test tubes.

The findings appear in the July 3rd issue of Cell.

Morphed Misfolding Proteins Found In Overlapping Neurodegenerative Diseases
Tau and alpha-synuclein protein clumps are hallmarks of separate diseases – Alzheimer’s and Parkinson’s, respectively. Yet these two proteins are often found entangled in diseased brains of patients who may manifest symptoms of both disorders.

One possible explanation for this convergence of Alzheimer’s and Parkinson’s disease pathology in the same patient is a global disruption in protein folding. But, Guo and Lee showed that one strain of alpha-synuclein fibrils which cannot promote tau fibrillization actually evolved into another strain that could efficiently cause tau to fibrillize in cultured neurons, although both strains are identical at the amino acid sequence level. Guo and Lee called the starting conformation “Strain A,” and the evolved conformation, “Strain B.”

To figure out how A and B differ, Guo showed that the two strains folded into different shapes, as indicated by their differential reactivity to antibodies and sensitivity to protein-degrading enzymes. The two strains also differed in their ability to promote tau fibrillization and pathology in mouse brains, mimicking the results from cultured cells. When analyzing post-mortem brains of Parkinson’s patients, the team found at least two distinct forms of pathological alpha-synuclein.

Lee and her team speculate that in humans, alpha-synuclein aggregates may shift their shapes as they pass from cell to cell (much like a cube of silly putty being re-shaped to form a sphere), possibly developing the ability to entangle other proteins such as tau along the way. That process, in turn, could theoretically yield distinct types of alpha-synuclein pathologies that are observed in different brain regions of Parkinson’s disease patients.

While further research is needed to confirm and extend these findings, they have potentially significant implications for patients afflicted with Parkinson’s and other neurodegenerative diseases. For example, Lee explains, they could account for some of the heterogeneity observed in Parkinson’s disease. Different strains of pathological alpha-synuclein may promote formation of distinct types of alpha-synuclein aggregates that may or may not induce tau pathology in different brain regions and in different patients. That, in turn, could explain why some Parkinson’s patients, for example, experience only motor impairments while others ultimately develop cognitive impairments.

The findings also have potential therapeutic implications, Lee says. By recognizing that pathological alpha-synuclein can exist in different forms that are linked with different impairments, researchers can now selectively target one or the other, or both, for instance with strain-selective antibodies.

“What we’ve found opens up new areas for developing therapies, and particularly immunotherapies, for Parkinson’s and other neurodegenerative diseases,” Lee says.

(Source: uphs.upenn.edu)

In a study that could change the way scientists view the process of protein production in humans, University of Chicago researchers have found a single gene that encodes two separate proteins from the same sequence of messenger RNA.

Published online July 3 in Cell, their finding elucidates a previously unknown mechanism in human gene expression and opens the door for new therapeutic strategies against a thus-far untreatable neurological disease.

"This is the first example of a mechanism in a higher organism in which one gene creates two proteins from the same mRNA transcript, simultaneously," said Christopher Gomez, MD, PhD, professor and chairman of the Department of Neurology at the University of Chicago, who led the study. "It represents a paradigm shift in our understanding of how genes ultimately encode proteins."

The human genome contains a similar number of protein-coding genes as the nematode worm (roughly 20,000). This disparity between biological complexity and gene count partially can be explained by the fact that individual genes can encode multiple protein variants via the production of different sequences of messenger RNA (mRNA) — short, mass-produced copies of genetic code that guide the creation of myriad cellular machinery.

Gomez and his team, which included first author Xiaofei Du, MD, discovered a new layer of complexity in this process of gene expression as they studied spinocerebellar ataxia type-6 (SCA6), a neurodegenerative disease that causes patients to slowly lose coordination of their muscles and eventually their ability to speak and stand. Human genetic studies identified its cause as a mutation in CACNA1A — a gene that encodes a calcium channel protein important for nerve cell function — resulting in extra copies of the amino acid glutamine.

However, although the gene, mutation and dysfunction are known, attempts to find the biological mechanism of the disease proved inconclusive. Calcium channel proteins with the mutation still seemed to function normally.

Suspecting another factor at play, Gomez and his team instead focused on α1ACT, a poorly understood, free-floating fragment of the CACNA1A calcium channel protein known to express extra copies of glutamine in SCA6 cells. The researchers first looked at its origin and found that, to their surprise, α1ACT was generated from the same mRNA sequence as the CACNA1A calcium channel.

For the first time, they had evidence of a human gene that coded one strand of mRNA that coded two separate, structurally distinct proteins. This occurred due to the presence of a special sequence in the mRNA known as an internal ribosomal entry site (IRES). Normally found at the beginning of an mRNA sequence, this IRES site sat in the middle, creating a second location for ribosomes, the cellular machines that read mRNA, to begin the process of protein production.

Looking at function, Gomez and his team found that normal α1ACT acted as a transcription factor and enhanced the growth of specific brain cells. Importantly, mutated α1ACT appeared to be toxic to nerve cells in a petri dish, and caused SCA6-like symptoms in an animal model.

The team hopes to discover other examples of human genes with similar IRES sites to better understand the implications of this new class of “bifunctional” genes on our basic biology. For now, they are focused on leveraging their findings toward helping SCA6 patients and already are working on ways to silence mutated α1ACT.

"We discovered this genetic phenomenon in the pursuit of a disease cause and, in finding it, immediately have a potential strategy for developing preclinical tools to treat that disease," Gomez said. "If we can target the IRES and inhibit production of this mutant form of α1ACT in SCA6, we may be able to stop the progression of the disease."

(Source: uchospitals.edu)

The results of the study may bear significance in the treatment of Alzheimer’s disease and cancer

Dysfunction of the ubiquitin-proteasome system is related to many severe neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, and certain types of cancer. Such dysfunction is also believed to be related to some degenerative muscle diseases.

The proteasome is a large protein complex that maintains cellular protein balance by degrading and destroying damaged or expired proteins. The ubiquitin is a small protein that labels proteins for destruction for the proteasome. If the system does not work effectively enough, expired and damaged proteins accumulate in the cell. If the system is overly active, it destroys necessary proteins in addition to unnecessary ones. In both cases, cell function is disturbed, and the cell may even die.

Proteasome activity is believed to decrease with ageing. However, not much is yet known about how proteasome activity is regulated in an aging multicellular organism. The research team of Academy Research Fellow, Docent Carina Holmberg-Still has discovered an important proteasome regulatory mechanism. The study was published in Cell Reports, a highly esteemed scientific journal.

"We examined whether proteasome activity is affected by insulin/IGF-1 signalling [IIS], which regulates aging in many organisms. The results show that decreased IIS increases proteasome activity," says Holmberg-Still.

Proteasome activity was studied in C. elegans, a free-living roundworm. Decreased IIS increases proteasome activity through the FOXO transcription factor DAF-16 and the UBH-4 enzyme. DAF-16 represses the expression of ubh-4 in certain cell types. The ubh-4 enzyme slows proteasome activity, which means that its repression accelerates proteasome activity.

"Using a cell culture model, we proved that the same mechanism works in human cells," says Holmberg-Still. When the expression of the uchl5 enzyme – the human equivalent of ubh-4 – was decreased, proteasome activity and the degradation of harmful proteins increased.

"Our study shows that the effect of ageing and the related signalling pathway on proteasome activity is tissue-specific. This was a new and interesting discovery that bears great significance in terms of treatment opportunities," says researcher Olli Matilainen, who prepared his dissertation in Holmberg-Still’s research team.

The identification of proteins that regulate proteasome activity and an understanding of the regulatory mechanism offer new opportunities in treating diseases that involve proteasome dysfunction. According to Holmberg-Still, proteins that regulate proteasome activity are particularly interesting in terms of medicine development.

"An ability to accelerate proteasome activity could be beneficial in the treatment of neurodegenerative diseases. Targeted proteasome inhibitors would be useful in the treatment of cancer – general proteasome inhibitors are already used as cancer medication to some extent, but they often have harmful side effects, because they cannot be targeted to a specific tissue."

Holmberg-Still’s team continues to investigate tissue-specific mechanisms that regulate proteasome activity. The team collaborates with clinical researchers to confirm whether its research results can be refined for clinical use.

(Source: eurekalert.org)

In a perspective piece appearing today in the journal Science, researchers at University of Rochester Medical Center (URMC) point to a newly discovered system by which the brain removes waste as a potentially powerful new tool to treat neurological disorders like Alzheimer’s disease. In fact, scientists believe that some of these conditions may arise when the system is not doing its job properly. 

“Essentially all neurodegenerative diseases are associated with the accumulation of cellular waste products,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the URMC Center for Translational Neuromedicine and author of the article. “Understanding and ultimately discovering how to modulate the brain’s system for removing toxic waste could point to new ways to treat these diseases.”   

The body defends the brain like a fortress and rings it with a complex system of gateways that control which molecules can enter and exit. While this “blood-brain barrier” was first described in the late 1800s, scientists are only now just beginning to understand the dynamics of how these mechanisms function. In fact, the complex network of waste removal, which researchers have dubbed the glymphatic system, was only first disclosed by URMC scientists last August in the journal Science Translational Medicine.  

The removal of waste is an essential biological function and the lymphatic system – a circulatory network of organs and vessels – performs this task in most of the body. However, the lymphatic system does not extend to the brain and, consequently, researchers have never fully understood what the brain does its own waste. Some scientists have even speculated that these byproducts of cellular function where somehow being “recycled” by the brain’s cells.  

One of the reasons why the glymphatic system had long eluded comprehension is that it cannot be detected in samples of brain tissue. The key to discovering and understanding the system was the advent of a new imaging technology called two-photon microscopy which enables scientists to peer deep within the living brain. Using this technology on mice, whose brains are remarkably similar to humans, Nedergaard and her colleagues were able to observe and document what amounts to an extensive, and heretofore unknown, plumbing system responsible for flushing waste from throughout the brain. 

The brain is surrounded by a membrane called the arachnoid and bathed in cerebral spinal fluid (CSF). CSF flows into the interior of the brain through the same pathways as the arteries that carry blood. This parallel system is akin to a donut shaped pipe within a pipe, with the inner ring carrying blood and the outer ring carrying CSF. The CSF is draw into brain tissue via a system of conduits that are controlled by a type support cells in the brain known as glia, in this case astrocytes. The term glymphatic was coined by combining the words glia and lymphatic.

The CSF is flushed through the brain tissue at a high speed sweeping excess proteins and other waste along with it. The fluid and waste are exchanged with a similar system that parallels veins which carries the waste out of the brain and down the spine where it is eventually transferred to the lymphatic system and from there to the liver, where it is ultimately broken down.

While the discovery of the glymphatic system solved a mystery that had long baffled the scientific community, understanding how the brain removes waste – both effectively and what happens when this system breaks down – has significant implications for the treatment of neurological disorders.

One of the hallmarks of Alzheimer’s disease is the accumulation in the brain of the protein beta amyloid. In fact, over time these proteins amass with such density that they can be observed as plaques on scans of the brain. Understanding what role the glymphatic system plays in the brain’s inability to break down and remove beta amyloid could point the way to new treatments. Specifically, whether certainly key ‘players’ in the glymphatic system, such as astrocytes, can be manipulated to ramp up the removal of waste.

“The idea that ‘dirty brain’ diseases like Alzheimer may result from a slowing down of the glymphatic system as we age is a completely new way to think about neurological disorders,” said Nedergaard. “It also presents us with a new set of targets to potentially increase the efficiency of glymphatic clearance and, ultimately, change the course of these conditions.”