In a new study in mice, a scientific collaboration centred at Brown University lays out in unprecedented detail a neurological signalling breakdown in Angelman syndrome, a disorder that affects thousands of children each year, characterised by developmental delay, seizures, and other problems. With the new understanding, the team demonstrated how a synthesised, peptide-like compound called CN2097 works to restore neural functions impaired by the disease.
‘I think we are really beginning to understand what’s going wrong. That’s what’s very exciting,’ said John Marshall, professor of medical science in the Department of Molecular Pharmacology, Physiology, and Biotechnology and the senior author of the study. However Marshall did caution that it is too early to predict how soon a clinical therapy might arise from the results.
In mice and people, Angelman syndrome arises from flaws in a gene called Ube3A. When it functions properly, the gene limits the amount of a protein called Arc in the brain. Left unchecked by the disease, Arc impairs the development of synapses in the hippocampus. Those neural connections may be essential for proper learning and memory function.
In the new study, Marshall and his colleagues report a series of experiments that show how the abundance of Arc creates such negative effects and how Arc might possibly be defeated and its ill-effects repaired in the lab.
Essentially, Arc interferes with the operation of a synaptic protein called PSD-95, that is required for the actions of a growth factor, known as brain-derived neurotrophic factor (BDNF). This growth factor is released at synaptic contacts and initiates a sequence of molecular interactions necessary for the strengthening of neuronal connections or synapses. In mice with the flawed Ube3A gene, the signals sent by BDNF for memory formation are disrupted.
Although the researchers were surprised by the details they discovered about how Arc hinders the signalling process, they didn’t come to the insight with complete naivete.
In other work, Marshall had been studying CN2097, designed by co-author Mark Spaller of Dartmouth College (Spaller synthesised it during earlier tenures at Wayne State University and Brown). The compound, which binds to PSD-95 was predicted to protect neurons under conditions of stroke and in disease states such as multiple sclerosis. With co-senior author Dennis Goebel of Wayne State, Marshall and Spaller found this to be the case. During the course of those studies the Marshall group learned that CN2097 enhanced the action of brain-derived neurotrophic factor (BDNF) which is known to be critically involved in long-term potentiation (LTP), a phenomenon believed by many neuroscientists to underlie learning.
Then, when University of North Carolina professor and former Brown postdoc Ben Philpot, now a leading expert on Angelman syndrome, returned to campus in 2008 to speak about Angelman syndrome, he showed how LTP is notably lacking in mice with the condition. After discussions with Philpot, Marshall and his group decided to test whether CN2097 might restore LTP in Angelman mice.
Early on, Marshall said, the team figured the defect in LTP in Angelman mice effect had to do with BDNF signalling.
‘We started studying BDNF signalling in the Angelman syndrome mouse and discovered the signalling was defective, so that really was the breakthrough,’ he said. ‘It was completely unexpected. It’s a new way of thinking about this disease.’
That led to the set of experiments now reported, in which the group found that CN2097 essentially protects PSD-95 from interference by Arc, helping to restore BDNF signaling and the formation of stronger synapses. In electrophysiological tests on hippocampal tissue of healthy and Angelman mice, the compound made obtaining LTP significantly easier, although observing LTP in Angelman mice is still more difficult than in normal mice, Marshall said. Brown University

Scientists at The University of Manchester have made important advances in understanding why our immune system can attack our own tissues resulting in eye and kidney diseases. It is hoped the research will pave the way for the development of new treatments for the eye condition age-related macular degeneration (AMD) and the kidney condition atypical Haemolytic Uremic Syndrome (aHUS).
Both AMD, which affects around 50 million people worldwide, and aHUS, a rare kidney disease that affects children, are associated with incorrectly controlled immune systems. A protein called complement factor H (CFH) is responsible for regulating part of our immune system called the complement cascade. Genetic alterations in CFH have been shown to increase a person’s risk of developing either AMD or aHUS, but rarely both. Why this is the case has never been explained until now.
Researchers from the Wellcome Trust Centre for Cell Matrix Research and the Ophthalmology and Vision Research Group in The University of Manchester’s Institute of Human Development have been expanding on their previous work that demonstrated a single common genetic alteration in CFH prevents it from fully protecting the back of the human eye. The research teams of Professor Tony Day and Professor Paul Bishop found that a common genetically altered form of CFH associated with AMD couldn’t bind properly to a layer under the retina called Bruch’s membrane. Having a reduced amount of CFH in this part of the eye leads to low-level inflammation and tissue damage, eventually resulting in AMD.
However, this mutation that changes CFH function in the eye has no affect on the protein’s ability to regulate the immune system in the kidney. A cluster of genetic mutations in a completely different part of CFH are associated with the kidney disease aHUS, but these have no affect on the eyes.
In their most recent study, which was funded by the Medical Research, the Manchester researchers have identified why these mutations in CFH result in diseases in very specific tissues. Professor Day explains: ‘For the first time we’ve been able to identify why these protein mutations are so tissue specific. We’re hoping our discovery will open the door to the development of tissue specific treatments to help the millions of people diagnosed with AMD every year.’
The research team looked at the two parts of CFH affected by the mutations. Both regions are capable of recognising host tissues, through interacting with sugars called glycosaminoglycans (GAGs). Successfully recognising these GAGs lets CFH build up a protective layer on the surface of our tissues that prevents our own immune system from attacking them.
It had always been believed that the region with mutations associated with aHUS was the most important for host recognition and for years people have been researching how to readdress immune dysregulation based on this belief. However, the recent discovery of a single common genetic alteration in the other part of CFH that is associated with eye disease raised the possibility that this previous opinion was not fully accurate. The University of Manchester

In laboratory studies, scientists at the Johns Hopkins Kimmel Cancer Center have developed a way to personalise chemotherapy drug selection for cancer patients by using cell lines created from their own tumors.
If the technique is successful in further studies, it could replace current laboratory tests to optimise drug selection that have proven technically challenging, of limited use, and slow, the researchers say.
Oncologists typically choose anticancer drugs based on the affected organs’ location and/or the appearance and activity of cancer cells when viewed under a microscope. Some companies offer commercial tests on surgically removed tumours using a small number of anticancer drugs. But Anirban Maitra, MBBS, professor of pathology and oncology at the Johns Hopkins University School of Medicine, says the tissue samples used in such tests may have been injured by anaesthetic drugs or shipping to a lab, compromising test results.
By contrast, he says ‘our cell lines better and more accurately represent the tumours, and can be tested against any drug library in the world to see if the cancer is responsive.’
The Johns Hopkins scientists developed their test-worthy cell lines by injecting human pancreatic and ovarian tumour cells into mice genetically engineered to favour tumour growth. Once tumours grew to one centimetre in diameter in the mice, the scientists transferred the tumours to culture flasks for additional studies and tests with anticancer drugs.
In one experiment, they successfully pinpointed the two anticancer drugs from among more than 3,000 that were the most effective in killing cells in one of the pancreatic cancer cell lines
The new method was designed to overcome one of the central problems of growing human tumour cell lines in a laboratory dish — namely the tendency of non-cancerous cells in a tumour to overgrow cancerous ones, says James Eshleman, M.D., Ph.D., professor of pathology and oncology and associate director of the Molecular Diagnostics Laboratory at Johns Hopkins. As a consequence, it has not been possible to conventionally grow cell lines for some cancers. Still other cell lines, Eshleman says, don’t reflect the full spectrum of disease.
To solve the problem of overcrowding by non-cancerous cells, Maitra and Eshleman bred genetically engineered mice that replace the non-cancerous cells with mouse cells that can be destroyed by chemicals, leaving pure human tumour cells for study.
‘Our technique allows us to produce cell lines where they don’t now exist, where more lines are needed, or where there is a particularly rare or biologically distinctive patient we want to study,’ says Eshleman. John Hopkin’s Hospital

New findings by Columbia researchers suggest that along with amyloid deposits, white matter hyperintensities (WMHs) may be a second necessary factor for the development of Alzheimer’s disease.

Most current approaches to Alzheimer’s disease focus on the accumulation of amyloid plaque in the brain. The researchers at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, led by Adam M. Brickman, PhD, assistant professor of neuropsychology, examined the additional contribution of small-vessel cerebrovascular disease, which they visualised as white matter hyperintensities (WMHs).

The study included 20 subjects with clinically defined Alzheimer’s disease, 59 subjects with mild cognitive impairment, and 21 normal control subjects. Using data from the Alzheimer’s Disease Neuro-imaging Initiative public database, the researchers found that amyloid and WHMs were equally associated with an Alzheimer’s diagnosis. Amyloid and WMHs were also equally predictive of which subjects with mild-cognitive impairment would go on to develop Alzheimer’s. Among those with significant amyloid, WMHs were more prevalent in those with Alzheimer’s than in normal control subjects.
Because the risk factors for WMHs—which are mainly vascular—can be controlled, the findings suggest potential ways to prevent the development of Alzheimer’s in those with amyloid deposits. Columbia University Medical Center

Psychogenic diseases, formerly known as ‘hysterical’ illnesses, can have many severe symptoms such as painful cramps or paralysis but without any physical explanation. However, new research from the University of Cambridge and UCL (University College London) suggests that individuals with psychogenic disease, that is to say physical illness that stems from emotional or mental stresses, do have brains that function differently.

Psychogenic diseases may look very similar to illnesses caused by damage to nerves, the brain or the muscles, or similar to genetic diseases of the nervous system. However, unlike organic diseases, psychogenic diseases do not have any apparent physical cause, making them difficult to diagnose and even more difficult to treat.

‘The processes leading to these disorders are poorly understood, complex and highly variable. As a result, treatments are also complex, often lengthy and in many cases there is poor recovery. In order to improve treatment of these disorders, it is important to first understand the underlying mechanism,’ said Dr James Rowe from the University of Cambridge.

The study looked at people with either psychogenic or organic dystonia, as well as healthy people with no dystonia. Both types of dystonia caused painful and disabling muscle contractions affecting the leg. The organic patient group had a gene mutation (the DYT1 gene) that caused their dystonia. The psychogenic patients had the symptoms of dystonia but did not have any physical explanation for the disease, even after extensive investigations.

The scientists performed PET brain scans on the volunteers at UCL, to measure the blood flow and brain activity of both of the groups, and healthy volunteers. The participants were scanned with three different foot positions: resting, moving their foot, and holding their leg in a dystonic position. The electrical activity of the leg muscles was measured at the same time to determine which muscles were engaged during the scans.

The researchers found that the brain function of individuals with the psychogenic illness was not normal. The changes were, however, very different from the brains of individuals with the organic (genetic) disease.

Dr Anette Schrag, from UCL, said: ‘Finding abnormalities of brain function that are very different from those in the organic form of dystonia opens up a way for researchers to learn how psychological factors can, by changing brain function, lead to physical problems.’

Dr Rowe added: ‘What struck me was just how very different the abnormal brain function was in patients with the genetic and the psychogenic dystonia. Even more striking was that the differences were there all the time, whether the patients were resting or trying to move.’

Additionally, the researchers found that one part of the brain previously thought to indicate psychogenic disease is unreliable: abnormal activity of the prefrontal cortex was thought to be the hallmark of psychogenic diseases. In this study, the scientists showed that this abnormality is not unique to psychogenic disease, since activity was also present in the patients with the genetic cause of dystonia when they tried to move their foot.

Dr Arpan Mehta, from the University of Cambridge, said: ‘It is interesting that, despite the differences, both types of patient had one thing in common – a problem at the front of the brain. This area controls attention to our movements and although the abnormality is not unique to psychogenic dystonia, it is part of the problem.’

This type of illness is very common. Dr Schrag said: ‘One in six patients that see a neurologist has a psychogenic illness. They are as ill as someone with organic disease, but with a different cause and different treatment needs. Understanding these disorders, diagnosing them early and finding the right treatment are all clearly very important. We are hopeful that these results might help doctors and patients understand the mechanism leading to this disorder, and guide better treatments.’ University of Cambridge