Posts tagged chaperone
Articles and news from the latest research reports.
Researchers find that drug used for another disease slows progression of Parkinson’s
A new study from UCLA found that a drug being evaluated to treat an entirely different disorder helped slow the progression of Parkinson’s disease in mice.
The study, published in the October edition of the journal Neurotherapeutics, found that the drug, AT2101, which has also been studied for Gaucher disease, improved motor function, stopped inflammation in the brain and reduced levels of alpha-synuclein, a protein critically involved in Parkinson’s.
Although the exact cause of Parkinson’s is unknown, evidence points to an accumulation of alpha-synuclein, which has been found to be common to all people with the disorder. The protein is thought to destroy the neurons in the brain that make dopamine, a neurotransmitter that helps regulate a number of functions, including movement and coordination. Dopamine deficiency is associated with Parkinson’s disease.
Gaucher disease is a rare genetic disorder in which the body cannot produce enough of an enzyme called β-glucocerebrosidase, or GCase. Researchers seeking genetic factors that increase people’s risk for developing Parkinson’s have determined that there may be a close relationship between Gaucher and Parkinson’s due to a GCase gene. Mutation of this gene, which leads to decreased GCase activity in the brain, has been found to be a genetic risk factor for Parkinson’s, although the majority of patients with Parkinson’s do not carry mutations in the Gaucher gene.
“This is the first time a compound targeting Gaucher disease has been tested in a mouse model of Parkinson’s disease and was shown to be effective,” said the study’s senior author, Marie-Francoise Chesselet, the Charles H. Markham Professor of Neurology at UCLA and director of the UCLA Center for the Study of Parkinson’s Disease. “The promising findings in this study suggest that further investigation of this compound in Parkinson’s disease is warranted.”
In the study, the researchers used mice that were genetically engineered to make too much alpha-synuclein which, over time, led the animals to develop deficits similar to those observed in humans with Parkinson’s. The researchers found that the mice’s symptoms improved after they received AT2101 for four months.
The researchers also observed that AT2101 was effective in treating Parkinson’s in mice even though they did not carry a mutant version of the Gaucher gene, suggesting that the compound may have a clinical effect in the broader Parkinson’s population.
AT2101 is a first-generation “pharmacological chaperone” — a drug that can bind malfunctioning, mutated enzymes and lead them through the cell to their normal location, which allows the enzymes to carry on with their normal work. This was the first time that a pharmacological chaperone showed promise in a model of Parkinson’s, according to Chesselet.
Parkinson’s disease affects as many as 1 million Americans, and 60,000 new cases are diagnosed each year. The disorder continues to puzzle scientists. There is no cure and researchers have been unable to pin down its cause and no drug has been proven to stop the progression of the disease, which causes tremors, stiffness and other debilitating symptoms. Current Parkinson’s treatments only address its symptoms.
(Source: newsroom.ucla.edu)
New headway in battle against neurodegenerative diseases
Conditions which may accelerate the spread of Parkinson’s disease, and a potential means of enhancing naturally-occurring defences against neurodegenerative disorders, have been identified in two new studies.
Two significant breakthroughs which could inform future treatments for neurodegenerative diseases such as Alzheimer’s and Parkinson’s, have been announced by scientists.
The research, published in two separate studies this week, advances understanding of the early development of such disorders and how they might be prevented – in particular by identifying the biological areas and processes that could be pinpointed by future drugs.
Both sets of results have emerged from collaborations between the research groups led by Chris Dobson, Tuomas Knowles and Michele Vendruscolo at the University of Cambridge, who focus on understanding protein “misfolding” diseases. These include Alzheimer’s and Parkinson’s diseases, as well as numerous others.
The first study provides evidence that the early spread of the protein aggregates associated with Parkinson’s appears to happen at an accelerated rate in mildly acidic conditions. This suggests that particular compartments within brain cells, which are slightly more acidic than others, may turn out to be appropriate targets for future treatments fighting the disease.
Meanwhile, researchers behind the second study appear to have identified a way in which the effectiveness of so-called molecular “chaperones”, responsible for limiting the damage caused by misfolded proteins, can be significantly enhanced.
The papers appear in the latest issue of Proceedings of the National Academy of Sciences of the USA.
As the term suggests, protein misfolding diseases stem from the fact that proteins, which need to fold into a particular shape to carry out their assigned function in the body, can sometimes misfold. In certain cases these misfolded proteins then clump together into fibre-like threads, called amyloid fibrils, potentially becoming toxic to other cells.
How this formation begins at a molecular level is still not completely understood, but comprehending the process will be fundamental to the development of future therapies and is the subject of extensive current research.
The first of the new studies builds on research published in 2013, which showed that in Alzheimer’s sufferers, the initial “nucleation” between proteins, which leads to amyloid formation, is followed by an amplification process called secondary nucleation. In these secondary events, the existing amyloid structures facilitate the formation of new aggregates, leading to their exponential increase. This process is likely to be at the heart of the development and spread of the disease in affected brains.
Using the same techniques, the researchers behind the latest study identified a similar process that is relevant in the early stage development of Parkinson’s Disease. Their work focused on a protein called α-synuclein, which is associated with the disorder, and simulated different conditions in which this protein might misfold and form clumps.
As with the previous study on Alzheimer’s, the research identified that Parkinson’s could spread through a series of secondary nucleation events. In addition, however, it showed that in the case of α-synuclein, this happens at a highly accelerated rate only in solutions which are mildly acidic, with a pH below 5.8. The finding is important because certain sub-compartments within cells are more acidic than others, meaning that these may be particularly productive areas for future treatments to target.
Dr Tuomas Knowles, from the Department of Chemistry and a Fellow of St John’s College, Cambridge, said: “This tells us much more about the molecular mechanisms underlying protein aggregation in Parkinson’s and suggests that mildly acidic microenvironments within cells may enhance that process by several orders of magnitude. Not every sub-cellular compartment offers these conditions, so it takes us much closer to understanding how the disease might spread.”
The second study meanwhile suggests a potential route to improving the effectiveness of a particular molecular “chaperone” – a loose classification for proteins which assist in the folding of others, thereby preventing them from causing damage when they misfold.
The researchers focused on a chaperone called α2-macroglobulin (α2M), which is found outside cells themselves. This is important because neurodegenerative diseases often stem from a process which begins with extracellular misfolding. The α2M was tested on a substrate of the amyloid-beta peptide associated with Alzheimer’s Disease.
Typically, the potency of α2M is limited. The new study, however, found that when it comes into contact with the oxidant hypochlorite – the same chemical found in household bleach, which also naturally occurs in our immune systems – its structure is modified in a manner that makes it into a much more dynamic defence.
In their report, the researchers suggest that this increased effectiveness stems from the fact that α2M, which is usually found in a four-part, “tetrameric” form, breaks down into “dimeric”, two-part forms when it comes into contact with hypochlorite.
The chaperone usually plays its role by preventing a misfolded protein from interacting with the membranes that surround and protect cells. Once in its dimeric form, however, receptor binding sites within the α2M are exposed, leading to specific interactions with receptors on the cell itself. If the α2M has already interacted with misfolded proteins, this connection triggers the cell to break the potentially harmful protein down.
“It’s almost like a warning flag for the cell, telling it that something is wrong,” Dr Janet Kumita, from the Department of Chemistry, explained. “It triggers the cell to react in a way that subjects the cargo of misfolded protein to a degradation pathway.”
“Increasing its potency in this way is an exciting prospect. If we could find a way of developing a drug that introduces the same structural alterations, we would have a therapeutic intervention capable of increasing this protective activity in patients with Alzheimer’s Disease.”
Professor Christopher Dobson, from the University’s Department of Chemistry and Master of St John’s College, said: “These studies add very substantially to our detailed understanding of the molecular origins of neurodegenerative diseases, which are now becoming one of the greatest threats to healthcare in the modern world.”
“We are beginning to understand exactly how a single, aberrant event can lead to the proliferation and spreading of toxic species throughout the brain, and the manner in which our sophisticated defence mechanisms do their best to suppress such phenomena. It will undoubtedly provide vital clues to the development in due course of new and effective drugs to combat these debilitating and increasingly common disorders.”
Aging brains need ‘chaperone’ proteins
The word “chaperone” refers to an adult who keeps teenagers from acting up at a dance or overnight trip. It also describes a type of protein that can guard the brain against its own troublemakers: misfolded proteins that are involved in several neurodegenerative diseases.
Researchers at Emory University School of Medicine have demonstrated that as animals age, their brains are more vulnerable to misfolded proteins, partly because of a decline in chaperone activity.
The researchers were studying a model of spinocerebellar ataxia, but the findings have implications for understanding other diseases, such as Alzheimer’s, Parkinson’s and Huntington’s. They also identified targets for potential therapies: bolstering levels of either a particular chaperone or a growth factor in brain cells can protect against the toxic effects of misfolded proteins.
The results were published this week in the journal Neuron.
Scientists led by Shihua Li, MD, and Xiao-Jiang Li, MD, PhD devised a system in which production of a misfolding-prone protein that causes a form of spinocerebellar ataxia can be triggered artificially in mice at various ages. Both Li’s are professors of human genetics at Emory University School of Medicine. The first author of the paper is BCDB graduate student Su Yang.
Spinocerebellar ataxia is an inherited neurodegenerative disease in which patients develop gait problems and a loss of coordination in mid-life, because of atrophy of the cerebellum. There are several types, each caused by a mutation in a different gene.
Most of the mutations that cause spinocerebellar ataxia involve an expansion of a “polyglutamine repeat" in a protein. Having the same protein building block (the amino acid glutamine) repeated dozens of times alters the protein’s function and makes it more likely to misfold and clump together. The misfolded proteins are toxic and interfere with the normal forms of the same protein.
Huntington’s disease is caused by a similar polyglutamine repeat. Misfolded proteins also play roles in Alzheimer’s and Parkinson’s, although their production is not driven by an inherited polyglutamine repeat in those diseases.
Li’s team was trying to distinguish between two possibilities. One was that the duration of mutant protein accumulation is important for disease severity; aging might allow more misfolded proteins to accumulate and become toxic over time.
Instead, the scientists observed that older animals develop disease more quickly after mutant protein production is triggered. The mutant protein accumulates more quickly in 9- and 14-month old mice than in 3-month old mice, suggesting that aged neurons are more vulnerable to the effects of the misfolded protein.
Chaperones are proteins whose job is to “prevent improper liaisons" between other proteins; they prevent the sticky regions of proteins from grabbing something they’re not supposed to. Li’s team identified a particular chaperone called Hsc70 whose activity declines with age in the brain, while others’ activity does not.
To confirm Hsc70’s importance, the researchers showed that boosting cells’ levels of Hsc70 can bolster their ability to cope with misfolded proteins. Injecting mice in the cerebellum with a virus that forces cells to make more Hsc70 can slow degeneration. The researchers found that the mutant protein interferes with production of a growth factor called MANF (mesenchephalic astrocyte-derived neurotrophic factor) in the cerebellum and that Hsc70 can prevent this interference. Injection of a virus that forces cells to make more MANF can also slow degeneration.
Potentially, small molecules that increase Hsc70 or MANF levels could be used for treating spinocerebellar ataxia, says Xiao-Jiang Li.
(Source: news.emory.edu)