Posts tagged neuroscience

An enzyme that could represent a powerful new tool for combating Alzheimer’s disease has been discovered by researchers at Mayo Clinic in Florida. The enzyme — known as BACE2 — destroys beta-amyloid, a toxic protein fragment that litters the brains of patients who have the disease. The findings were published online Sept. 17 in the science journal Molecular Neurodegeneration.

Alzheimer’s disease is the most common memory disorder. It affects more that 5.5 million people in the United States. Despite the disorder’s enormous financial and personal toll, effective treatments have not yet been found.

The Mayo research team, led by Malcolm A. Leissring, Ph.D., a neuroscientist at Mayo Clinic in Florida, made the discovery by testing hundreds of enzymes for the ability to lower beta-amyloid levels. BACE2 was found to lower beta-amyloid more effectively than all other enzymes tested. The discovery is interesting because BACE2 is closely related to another enzyme, known as BACE1, involved in producing beta-amyloid.

“Despite their close similarity, the two enzymes have completely opposite effects on beta-amyloid — BACE1 giveth, while BACE2 taketh away,” Dr. Leissring says.

Beta-amyloid is a fragment of a larger protein, known as APP, and is produced by enzymes that cut APP at two places. BACE1 is the enzyme responsible for making the first cut that generates beta-amyloid. The research showed that BACE2 cuts beta-amyloid into smaller pieces, thereby destroying it, instead. Although other enzymes are known to break down beta-amyloid, BACE2 is particularly efficient at this function, the study found.

Previous work had shown that BACE2 can also lower beta-amyloid levels by a second mechanism: by cutting APP at a different spot from BACE1. BACE2 cuts in the middle of the beta-amyloid portion, which prevents beta-amyloid production.

“The fact that BACE2 can lower beta-amyloid by two distinct mechanisms makes this enzyme an especially attractive candidate for gene therapy to treat Alzheimer’s disease,” says first author Samer Abdul-Hay, Ph.D., a neuroscientist at Mayo Clinic in Florida.

The discovery suggests that impairments in BACE2 might increase the risk of Alzheimer’s disease. This is important because certain drugs in clinical use — for example, antiviral drugs used to treat human immunodeficiency virus (HIV) — work by inhibiting enzymes similar to BACE2.

Although BACE2 can lower beta-amyloid by two distinct mechanisms, only the newly discovered mechanism — beta-amyloid destruction — is likely relevant to the disease, the researchers note. This is because the second mechanism, which involves BACE2 cutting APP, does not occur in the brain. The researchers have obtained a grant from the National Institutes of Health to study whether blocking beta-amyloid destruction by BACE2 can increase the risk for Alzheimer’s disease in a mouse model of the disease.

(Source: newswise.com)

One small change to the DNA sequence can cause more weighty changes to the human body, according to a new study released today. The discovery comes thanks to a worldwide consortium of researchers that includes Professor and Chair of Quantitative Genetics at The University of Queensland (UQ), Peter Visscher, from the Queensland Brain Institute (QBI) and Diamantina Institute (DI) at UQ.

He and his team have found a single change in genetic sequence at the gene FTO had a significant effect on the variability of body mass index (BMI). BMI is a commonly used measure of obesity. It measures someone’s weight adjusted for his or her height.

Professor Visscher said that the genetic change, called a single nucleotide polymorphism (SNP), was the replacement of one nucleotide – the units that make up our DNA – with another. “They are the most abundant type of variation in the human genome,” he said. “SNPs occur normally throughout our DNA and most have no effect on our health, however, we’ve found one that does have a small but significant effect on variation in BMI.”

After analysing data from almost 170,000 people, he and his team established that those with a sequence variant in the FTO gene not only weighed more on average, but the measured weights varied more than in the group without the variant. The variability of BMI within the group with two copies of the variant was, in fact, 7 per cent larger than the group without the variant.

Professor Visscher said this equated to around half a kilogram difference in the standard deviation of weight. “So as a group, people with two copies of the weight increasing variant are a few kilograms heavier and vary more,” he said. Genetic differences in variability of specific traits have been seen in many plant and animal species but specific genes or mechanisms to explain the phenomenon had not been identified.

Professor Visscher’s study is the first to look systematically at genetic effects on variation of a complex trait in humans using a very large sample size. “The study is important because it demonstrates that genes can be found that affect trait variability. “This is a first step towards understanding how genes control variation,” Professor Visscher said.

This study is also the first to offer researchers an indirect method to measure genotype by environment interactions without having a measure of specific environmental factors. “If a gene interacts with specific environmental factors then this can be observed with our method,” Professor Visscher said.

“For example, if the effect of a gene on weight is smaller in people who physically exercise than in people who do not, then this will lead to less variation among people with two copies of the weight decreasing variant.

“In our study we did not measure specific environmental effects such as physical exercise so we can’t say for sure whether our results are due to a genotype-environment interaction.”

This is the second study Professor Visscher has published in the prestigious journal Nature this year. Earlier this year he identified that genetic differences also affect how intelligence changes across a lifetime. The work also suggested these changes in intelligence were largely influenced by environmental factors.

(Source: uq.edu.au)

The rare disorder Wolfram syndrome is caused by mutations in a single gene, but its effects on the body are far reaching. The disease leads to diabetes, hearing and vision loss, nerve cell damage that causes motor difficulties, and early death.

Now, researchers at Washington University School of Medicine in St. Louis, the Joslin Diabetes Center in Boston and the Novartis Institutes for BioMedical Research report that they have identified a mechanism related to mutations in the WFS1 gene that affects insulin-secreting beta cells. The finding will aid in the understanding of Wolfram syndrome and also may be important in the treatment of milder forms of diabetes and other disorders.

The study is published online in the journal Nature Cell Biology

“We found something we didn’t expect,” says researcher Fumihiko Urano, MD, PhD, associate professor of medicine in Washington University’s Division of Endocrinology, Metabolism and Lipid Research. “The study showed that the WFS1 gene is crucial to producing a key molecule involved in controlling the metabolic activities of individual cells.” That molecule is called cyclic AMP (cyclic adenosine monophosphate).

Insulin-secreting beta cells in the pancreas (above) cannot make enough cyclic AMP in patients with Wolfram syndrome. As a result, the pancreas produces and secretes less insulin, and the cells eventually die.

In insulin-secreting beta cells in the pancreas, for example, cyclic AMP rises in response to high blood sugar, causing those cells to produce and secrete insulin.

“I would compare cyclic AMP to money,” Urano says. “You can’t just take something you make to the store and use it to buy food. First, you have to convert it into money. Then, you use the money to buy food. In the body, external signals stimulate a cell to make cyclic AMP, and then the cyclic AMP, like money, can ‘buy’ insulin or whatever else may be needed.”

The reason patients with Wolfram syndrome experience so many problems, he says, is because mutations in the WFS1 gene interfere with cyclic AMP production in beta cells in the pancreas.

“In patients with Wolfram syndrome, there is no available WFS1 protein, and that protein is key in cyclic AMP production,” he explains. “Then, because levels of cyclic AMP are low in insulin-secreting beta cells, those cells produce and secrete less insulin. And in nerve cells, less cyclic AMP can lead to nerve cell dysfunction and death.”

By finding that cyclic AMP production is affected by mutations in the WFS1 gene, researchers now have a potential target for understanding and treating Wolfram syndrome.

“I don’t know whether we can find a way to control cyclic AMP production in specific tissues,” he says. “But if that’s possible, it could help a great deal.”

Meanwhile, although Wolfram syndrome is rare, affecting about 1 in 500,000 people, Urano says the findings also may be important to more common disorders.

“It’s likely this mechanism is related to diseases such as type 2 diabetes,” he says. “If a complete absence of the WFS1 protein causes Wolfram syndrome, perhaps a partial impairment leads to something milder, like diabetes.”

(Source: news.wustl.edu)