Alzheimer’s disease has proven to be a difficult enemy to defeat. After all, ageing is the No. 1 risk factor for the disorder, and there’s no stopping that. Most researchers believe the disease is caused by one of two proteins, one called tau, the other beta-amyloid. As we age, most scientists say, these proteins either disrupt signalling between neurons or simply kill them.
Now, a new UCLA study suggests a third possible cause: iron accumulation. Dr. George Bartzokis, a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA and senior author of the study, and his colleagues looked at two areas of the brain in patients with Alzheimer’s. They compared the hippocampus, which is known to be damaged early in the disease, and the thalamus, an area that is generally not affected until the late stages. Using sophisticated brain-imaging techniques, they found that iron is increased in the hippocampus and is associated with tissue damage in that area. But increased iron was not found in the thalamus.
While most Alzheimer’s researchers focus on the build-up of tau or beta-amyloid that results in the signature plaques associated with the disease, Bartzokis has long argued that the breakdown begins much further ‘upstream.’ The destruction of myelin, the fatty tissue that coats nerve fibres in the brain, he says, disrupts communication between neurons and promotes the build-up of the plaques. These amyloid plaques in turn destroy more and more myelin, disrupting brain signalling and leading to cell death and the classic clinical signs of Alzheimer’s.
Myelin is produced by cells called oligodendrocytes. These cells, along with myelin, have the highest levels of iron of any cells in the brain, Bartzokis says, and circumstantial evidence has long supported the possibility that brain iron levels might be a risk factor for age-related diseases like Alzheimer’s. Although iron is essential for cell function, too much of it can promote oxidative damage, to which the brain is especially vulnerable.
In the current study, Bartzokis and his colleagues tested their hypothesis that elevated tissue iron caused the tissue breakdown associated with Alzheimer’s disease. They targeted the vulnerable hippocampus, a key area of the brain involved in the formation of memories, and compared it to the thalamus, which is relatively spared by Alzheimer’s until the very late stages of disease.
The researchers used an MRI technique that can measure the amount of brain iron in ferritin, a protein that stores iron, in 31 patients with Alzheimer’s and 68 healthy control subjects.
In the presence of diseases like Alzheimer’s, as the structure of cells breaks down, the amount of water increases in the brain, which can mask the detection of iron, according to Bartzokis.
‘It is difficult to measure iron in tissue when the tissue is already damaged,’ he said. ‘But the MRI technology we used in this study allowed us to determine that the increase in iron is occurring together with the tissue damage. We found that the amount of iron is increased in the hippocampus and is associated with tissue damage in patients with Alzheimer’s but not in the healthy older individuals — or in the thalamus. So the results suggest that iron accumulation may indeed contribute to the cause of Alzheimer’s disease.’
But it’s not all bad news from this study, Bartzokis noted.
‘The accumulation of iron in the brain may be influenced by modifying environmental factors, such as how much red meat and iron dietary supplements we consume and, in women, having hysterectomies before menopause,’ he said.
In addition, he noted, medications that chelate and remove iron from tissue are being developed by several pharmaceutical companies as treatments for the disorder. This MRI technology may allow doctors to determine who is most in need of such treatments. University of California – Los Angeles

Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg and Regensburg University, both in Germany, and the University of Lisboa, in Portugal, have discovered a promising potential drug target for cystic fibrosis. Their work also uncovers a large set of genes not previously linked to the disease, demonstrating how a new screening technique can help identify new drug targets.

Cystic fibrosis is a hereditary disease caused by mutations in a single gene called CFTR. These mutations cause problems in various organs, most notably making the lining of the lungs secrete unusually thick mucus. This leads to recurrent life-threatening lung infections, which make it increasingly hard for patients to breathe. The disease is estimated to affect 1 in every 2500-6000 new-borns in Europe.

In patients with cystic fibrosis, the mutations to CFTR render it unable to carry out its normal tasks. Among other things, this means CFTR loses the ability to control a protein called the epithelial sodium channel (ENaC). Released from CFTR’s control, ENaC becomes hyperactive, cells in the lungs absorb too much sodium and – as water follows the sodium – the mucus in patients’ airways becomes thicker and the lining of the lungs becomes dehydrated. The only drug currently available that directly counteracts a cystic fibrosis-related mutation only works on the three percent of patients that carry one specific mutation out of the almost 2000 CFTR mutations scientists have found so far.

Thus, if you were looking for a more efficient way to fight cystic fibrosis, finding a therapy that would act upon ENaC instead of trying to correct that multitude of CFTR mutations would seem like a good option. But unfortunately, the drugs that inhibit ENaC, mostly developed to treat hypertension, don’t transfer well to cystic fibrosis, where their effects don’t last very long. So scientists at EMBL, Regensburg University and University of Lisboa set out to find alternatives.

‘In our screen, we attempted to mimic a drug treatment,’ says Rainer Pepperkok, whose team at EMBL developed the technique, ‘we’d knock down a gene and see if ENaC became inhibited.’

Starting with a list of around 7000 genes, the scientists systematically silenced each one, using a combination of genetics and automated microscopy, and analysed how this affected ENaC. They found over 700 genes which, when inhibited, brought down ENaC activity, including a number of genes no-one knew were involved in the process. Among their findings was a gene called DGKi. When they tested chemicals that inhibit DGKi in lung cells from cystic fibrosis patients, the scientists discovered that it appears to be a very promising drug target.

‘Inhibiting DGKi seems to reverse the effects of cystic fibrosis, but not block ENaC completely,’ says Margarida Amaral from the University of Lisboa, ‘indeed, inhibiting DGKi reduces ENaC activity enough for cells to go back to normal, but not so much that they cause other problems, like pulmonary oedema.’

These promising results have already raised the interest of the pharmaceutical industry and led the researchers to patent DGKi as a drug target, as they are keen to explore the issue further, searching for molecules that strongly inhibit DGKi without causing side-effects.

‘Our results are encouraging, but these are still early days,’ says Karl Kunzelmann from Regensburg University. ‘We have DGKi in our cells because it is needed, so we need to be sure that these drugs are not going to cause problems in the rest of the body.’ EMBL

French scientists have discovered that supposedly rare mutations in the mitochondria, the ‘power plants’ of human cells responsible for creating energy, account for more than 7% of patients with a mitochondrial disease manifesting itself as a respiratory deficiency. Their data emphasise the need for comprehensive analysis of all the mitochondrial DNA (mtDNA) in patients suspected as having a mitochondrial disease, and this should include children, a researcher will tell the annual conference of the European Society of Human Genetics.
Dr. Sylvie Bannwarth and Professor Véronique Paquis, from the Hôpital Archet 2, Nice, France, together with colleagues from the ten diagnostic centres that make up the French Mitochondrial Disease Network, investigated 743 patients who were suspected of having a respiratory chain disorder caused by defective mitochondria, but who did not carry a common mtDNA mutation. Mitochondrial diseases, which can be very severe, are estimated to affect one child in every 5000, and are usually untreatable. However, prompt diagnosis can help clinicians to prescribe treatment to alleviate secondary symptoms.

‘We examined the relationship between clinical presentation of disease, age at onset, and the localisations of mutations. Our results showed that, in the French population, clinical presentations that are not associated with common mtDA mutations begin mainly before adulthood, and that neuromuscular problems are the most common manifestation of such mutations’, says Dr. Bannwarth.

‘We found that early onset disease was significantly associated with mutations in genes that code for proteins, while late onset disorder were associated with mutations in tRNA genes, and that two genes represent ‘hotspots’ for disease-causing mutations. Knowing the prevalence of these rare mutations is essential if we are to be able to improve the diagnosis of these diseases.’

There are very many mitochondrial diseases, and they manifest themselves in a large number of different ways. They can involve muscle weakness, neurological disease, respiratory, gastrointestinal and cardiac problems, and strokes. Many are degenerative, while some are relatively static.

One of the two techniques used for screening the entirety of an individual’s mtDNA was developed by Dr. Bannwarth. The use of such techniques can aid not just in diagnosis, but also in genetic counselling and prenatal diagnosis for mitochondrial disease. Up to now the study of mtDNA mutations has usually been restricted to the detection of deletions and a few common mutations, but without any data about the prevalence of rare mutations and their associated phenotypes (characteristics or traits).

‘With the advent of Next Generation Sequencing techniques, screening all mtDNA is now feasible, and this means that we can detect both common and rare mutations as well as deletions. For example, in the patients we studied we found that Leigh syndrome – a rare disorder that affects the central nervous system – was found in 41% of patients with rare mtDNA mutations. Had we not screened all of the mtDNA, including the rare mutations, we would not have known this’, says Dr. Bannwarth. ‘This is clearly a big aid to accurate diagnosis and we hope that our results will underline the importance of comprehensive mtDNA screening.’ EurekAlert

Scientists from the Monell Center report the surprising finding that two proteins involved in oral taste detection also play a crucial role in sperm development.
‘This paper highlights a connection between the taste system and male reproduction,’ said lead author Bedrich Mosinger, MD, PhD, a molecular biologist at Monell. ‘It is one more demonstration that components of the taste system also play important roles in other organ systems.’
While breeding mice for taste-related studies, the researchers discovered that they were unable to produce offspring that were simultaneously missing two taste-signalling proteins.
As reported online, the critical proteins were TAS1R3, a component of both the sweet and umami (amino acid) taste receptors, and GNAT3, a molecule needed to convert the oral taste receptor signal into a nerve cell response.
Breeding experiments determined that fertility was affected only in males. Both taste proteins had previously been found in testes and sperm, but until now, their function there was unknown.
In order to explore the reproductive function of the two proteins, the research team engineered mice that were missing genes for the mouse versions of TAS1R3 and GNAT3 but expressed the human form of the TAS1R3 receptor. These mice were fertile.
However, when the human TAS1R3 receptor was blocked in the engineered mice by adding the drug clofibrate to the rodents’ diet, thus leaving the mice without any functional TAS1R3 or GNAT3 proteins, the males became sterile due to malformed and fewer sperm. The sterility was quickly reversed after clofibrate was removed from the diet.
Clofibrate belongs to a class of drugs called fibrates that frequently are prescribed to treat lipid disorders such as high blood cholesterol or triglycerides. Previous studies from the Monell team had revealed that it is a potent inhibitor of the human, but not mouse, TAS1R3 receptor.
Noting the common use of fibrates in modern medicine and also the widespread use in modern agriculture of the structurally-related phenoxy-herbicides, which also block the human TAS1R3 receptor, Mosinger speculates that these compounds could be negatively affecting human fertility, an increasing problem worldwide.
He in turn notes positive implications related to the research. ‘If our pharmacological findings are indeed related to the global increase in the incidence of male infertility, we now have knowledge to help us devise treatments to reduce or reverse the effects of fibrates and phenoxy-compounds on sperm production and quality. This knowledge could further be used to design a male non-hormonal contraceptive.’
Previous work from Monell and other groups has shown that some taste genes can be found in other parts of the body, including stomach, intestines, pancreas, lungs, and brain, where they are increasingly thought to have important physiological functions. Monell Center

Australian researchers have demonstrated a strong association between the FTO (fat and obesity) gene and hip fracture in women. While the gene is already well known to affect diabetes and body fat, this is the first study to show that its high-risk variant can increase the risk of hip fracture by as much as 82%.
The study, undertaken by Dr Bich Tran and Professor Tuan Nguyen from Sydney’s Garvan Institute of Medical Research, examined six gene variants (single nucleotide polymorphisms, or SNPs) of the FTO gene, taken from the DNA of 943 women in the Dubbo Osteoporosis Epidemiology Study (DOES). The women were all over 60, and their bone health was followed between 1989 and 2007. During that period, 102 women had hip fractures.
On average, the risk of fracture is about 11%. The study showed that if a woman has a low-risk genotype, or gene variant, the risk of fracture is 10%. If she has a high-risk genotype, it is 16%.
The authors believe that the findings have the potential to improve prediction of hip fracture. Known risk factors, also to be taken into account, include advancing age, falls, history of fracture, low bone mineral density, low body mass index (BMI) and genetic make-up.
‘We found that for a woman of the same age and same clinical risk factors, those with the high-risk genotype have an increased risk of fracture of 82% – a very high effect in genetic terms,’ said Professor Tuan Nguyen.
‘A genome-wide association study published in 2007 suggested that genetic variants in the FTO gene were associated with variation in BMI. This led us to hypothesise that they might also be associated with variation in hip fracture risk.’
‘The present study tested our hypothesis by examining the association between common variants in the FTO gene and hip fracture.’
‘Our results showed a strong association with hip fracture, with some gene variants doubling the risk of fracture. Interestingly, this was independent of both the bone density and BMI of the women we studied.’
‘We also found that the FTO gene expresses in bone cells, and may have something to do with bone turnover, or remodelling, although its exact mechanisms are unclear.’
‘It’s important to emphasise that, while promising, our finding is a first step. It will need to be replicated in other studies, and its mechanisms clearly understood before it is useful in drug development.’ Garvan Institute of Medical Research