Posts tagged protein

Misfolded proteins can cause various neurodegenerative diseases such as spinocerebellar ataxias (SCAs) or Huntington’s disease, which are characterized by a progressive loss of neurons in the brain. Researchers of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany, together with their colleagues of the Université Paris Diderot, Paris, France, have now identified 21 proteins that specifically bind to a protein called ataxin-1. Twelve of these proteins enhance the misfolding of ataxin-1 and thus promote the formation of harmful protein aggregate structures, whereas nine of them prevent the misfolding (PLoS Genetics).

Proteins only function properly when the chains of amino acids, from which they are built, fold correctly. Misfolded proteins can be toxic for the cells and assemble into insoluble aggregates together with other proteins. Ataxin-1, the protein that the researchers have now investigated, is very prone to misfolding due to inherited gene defects that cause neurodegenerative diseases. The reason for this is that the amino acid glutamine is repeated in the amino acid chain of ataxin-1 very often - the more glutamine, the more toxic the protein. Approximately 40 repeats of glutamine are considered to be toxic for the cells.

Now, Dr. Spyros Petrakis, Dr. Miguel Andrade, Professor Erich Wanker and colleagues have identified 21 proteins that mainly interact with ataxin-1 and influence its folding or misfolding. Twelve of these proteins enhance the toxicity of ataxin-1 for the nerve cells, whereas nine of the identified proteins reduce its toxicity.

Furthermore, the researchers detected a common feature in the structure of those proteins that enhances toxicity and aggregation. It is a special structure scientists call “coiled-coil-domain” because it resembles a double twisted spiral or helix. Apparently this structure promotes aggregation, because proteins that interact with ataxin-1 and have this domain enhance the toxic effect of mutated ataxin-1. As the researchers said, this structure could be a potential target for therapy: “A careful analysis of the molecular details could help to discover drugs that suppress toxic processes.”

(Source: mdc-berlin.de)

A drug designed for diabetes sufferers could have the potential to treat neurodegenerative diseases like Alzheimer’s, a study by scientists at the University of Ulster has revealed.

Type II diabetes is a known risk factor for Alzheimer’s and it is thought that impaired insulin signalling in the brain could damage nerve cells and contribute to the disease.

Scientists believe that drugs designed to tackle Type II diabetes could also have benefits for keeping our brain cells healthy.

To investigate this, Prof Christian Hölscher and his team at the Biomedical Sciences Research Institute on the Coleraine campus used an experimental drug called (Val8)GLP-1.

This drug simulates the activity of a protein called GLP-1, which can help the body control its response to blood sugar. The scientists treated healthy mice with the drug and studied its effects in the brain.

Although it is often difficult for drugs to cross from the blood into the brain, the team found that (Val8)GLP-1 entered the brain and appeared to have no side-effects at the doses tested.

The drug promoted new brain cells to grow in the hippocampus, an area of the brain known to be involved in memory. This finding suggests that as well as its role in insulin signalling, GLP-1 may also be important for the production of new nerve cells in the mouse brain.

The team found that blocking the effect of GLP-1 in the brain made mice perform more poorly on learning and memory task, while boosting it with the drug seemed to have no effect on behaviour.

The new findings, published this week in the journal Brain Research, are part of ongoing research funded by Alzheimer’s Research UK, the leading dementia research charity.

Prof Hölscher, said: “Here at the Biomedical Sciences Research Institute, we are really interested in the potential of diabetes drugs for protecting brain cells from damage and even promoting new brain cells to grow. This could have huge implications for diseases like Alzheimer’s or Parkinson’s, where brain cells are lost.

“It is very encouraging that the experimental drug we tested, (Val8)GLP-1, entered the brain and our work suggests that GLP-1 could be a really important target for boosting memory. While we didn’t see benefits on learning and memory in these healthy mice, we are keen to test the drugs in mice with signs of Alzheimer’s disease, where we could see real improvements.”

Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, said: “We are pleased to have supported this early stage research, suggesting that this experimental diabetes drug could also promote the growth of new brain cells. While we know losing brain cells is a key feature of Alzheimer’s, there is a long way to go before we would know whether this drug could benefit people with the disease.

"This research will help us understand the factors that keep nerve cells healthy, knowledge that could hold vital clues to tackling Alzheimer’s. With over half a million people in the UK living with the disease, learning more about how to keep our brain cells healthy is of vital importance. Funding for dementia research lags far behind that of other common diseases, but is essential if we are to realise the true potential of research like this.”

(Source: alphagalileo.org)

Measurements of five protein biomarkers in the cerebrospinal fluid helped to differentiate Alzheimer’s disease from Parkinson’s disease with dementia and from dementia with Lewy bodies in a cross-sectional study of individuals at Swedish neurology and memory disorder clinics.

The diagnostic accuracy of this panel of tests in distinguishing Alzheimer’s disease from dementia with Lewy bodies “is at least in the same order of magnitude as that obtained with dopamine transporter imaging, and with a lower cost,” Dr. Sara Hall of the department of clinical sciences, Lund (Sweden) University, Malmö, and her associates wrote in a study published Aug. 27 in Archives of Neurology.

In addition, one of the five biomarkers in this panel appears to differentiate Parkinson’s disease from atypical parkinsonism such as that seen in progressive supranuclear palsy, multiple system atrophy, or corticobasal degeneration, the researchers noted.

Their results confirmed those of previous studies postulating that CSF total tau (T-tau) and phophorylated tau (P-tau) levels are higher in Alzheimer’s than in the other two dementias, whereas amyloid-beta (Abeta) 1-42 levels are lower in Alzheimer’s than in the other two dementias.

(Source: acep.org)

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ScienceDaily (Aug. 16, 2012) — Researchers have found what they believe is the key to understanding why the human brain is larger and more complex than that of other animals.

The human brain, with its unequaled cognitive capacity, evolved rapidly and dramatically.

"We wanted to know why," says James Sikela, PhD, who headed the international research team that included researchers from the University of Colorado School of Medicine, Baylor College of Medicine and the National Institutes of Mental Health. "The size and cognitive capacity of the human brain sets us apart. But how did that happen?"

"This research indicates that what drove the evolutionary expansion of the human brain may well be a specific unit within a protein — called a protein domain — that is far more numerous in humans than other species."

The protein domain at issue is DUF1220. Humans have more than 270 copies of DUF1220 encoded in the genome, far more than other species. The closer a species is to humans, the more copies of DUF1220 show up. Chimpanzees have the next highest number, 125. Gorillas have 99, marmosets 30 and mice just one. “The one over-riding theme that we saw repeatedly was that the more copies of DUF1220 in the genome, the bigger the brain. And this held true whether we looked at different species or within the human population.”

Sikela, a professor at the CU medical school, and his team also linked DUF1220 to brain disorders. They associated lower numbers of DUF1220 with microcephaly, when the brain is too small; larger numbers of the protein domain were associated with macrocephaly, when the brain is too large.

The findings were reported today in the online edition of The American Journal of Human Genetics. The researchers drew their conclusions by comparing genome sequences from humans and other animals as well as by looking at the DNA of individuals with microcephaly and macrocephaly and of people from a non-disease population.

"The take home message was that brain size may be to a large degree a matter of protein domain dosage," Sikela says. "This discovery opens many new doors. It provides new tools to diagnose diseases related to brain size. And more broadly, it points to a new way to study the human brain and its dramatic increase in size and ability over what, in evolutionary terms, is a short amount of time."

Source: Science Daily

When something goes wrong in your brain, you’d think it would be a good idea to get rid of the problem. Turns out, sometimes it’s best to keep hold of it. By preventing faulty proteins from being destroyed, researchers have delayed the symptoms of a degenerative brain disorder.

SNAP25 is one of three proteins that together make up a complex called SNARE, which plays a vital role in allowing neurons to communicate with each other. In order to work properly, all the proteins must be folded in a specific way. CSP alpha is one of the key proteins that ensures SNAP25 is correctly folded.

Cells have a backup system to deal with any misfolded proteins – they are destroyed by a bell-shaped enzyme called a proteasome, which pulls the proteins inside itself and breaks them down.

People with a genetic mutation that affects the CSP alpha protein – and its ability to correctly fold SNAP25 – can develop a rare brain disorder called neuronal ceroid lipofuscinosis (NCL). The disorder causes significant damage to neurons – people affected gradually lose their cognitive abilities and struggle to move normally.

To find out what role proteasomes might play in NCL, Manu Sharma and his colleagues at Stanford University in California blocked the enzyme in mice that were bred to lack CSP alpha. “We weren’t sure what would happen,” says Sharma. Either the misfolded SNAP25 would accumulate and harm the cells, or some of the misfolded proteins may work well enough to retain some of their function.

Longer life

It appears it was the latter. Mice bred to lack CSP alpha suffer the same physical and cognitive problems as humans, and tend to survive for about 65 to 80 days, rather than the normal 670 days. But mice injected with a drug that blocked protease lived, on average, an extra 15 days. “Fifteen days might not sound like much, but as a percentage it’s quite significant,” says Sharma. What’s more, treated mice were able to stave off measurable movement and cognitive symptoms for an extra 10 days.

The finding goes against the idea that neurodegenerative disorders should be treated by clearing away misfolded proteins, rather than trying to rescue their function. “People normally think that protease isn’t working hard enough,” says Nico Dantuma at the Karolinska Institute in Stockholm, Sweden, who was not involved in the study.

But whether or not the drugs are likely to work in other neurodegenerative disorders involving aggregations of misfolded proteins, such as Alzheimer’s and Parkinson’s disease, is up for debate. “I don’t think their results prove that clearing misfolded proteins is not a useful therapeutic,” says Ana Maria Cuervo at Albert Einstein College of Medicine in New York. Other studies that increase the degrading of misfolded proteins have been shown to improve symptoms in other neurodegenerative diseases, she says.

"There are two sides of the coin," says Dantuma. "You might rescue functioning proteins from being degraded… but it’s too early to extrapolate these results to Alzheimer’s and Parkinson’s disease."

In the meantime, drugs that block proteasome are already used to treat cancer, so Sharma hopes they can soon be trialled in people with NCL.

Source: NewScientist