An Ottawa-led team of researchers describe the role of a specific gene, called Snf2h, in the development of the cerebellum. Snf2h is required for the proper development of a healthy cerebellum, a master control centre in the brain for balance, fine motor control and complex physical movements.

Athletes and artists perform their extraordinary feats relying on the cerebellum. As well, the cerebellum is critical for the everyday tasks and activities that we perform, such as walking, eating and driving a car. By removing Snf2h, researchers found that the cerebellum was smaller than normal, and balance and refined movements were compromised.

Led by Dr. David Picketts, a senior scientist at the Ottawa Hospital Research Institute and professor in the Faculty of Medicine at the University of Ottawa, the team describes the Snf2h gene, which is found in our brain’s neural stem cells and functions as a master regulator. When they removed this gene early on in a mouse’s development, its cerebellum only grew to one-third the normal size. It also had difficulty walking, balancing and coordinating its movements, something called cerebellar ataxia that is a component of many neurodegenerative diseases.

‘As these cerebellar stem cells divide, on their journey toward becoming specialized neurons, this master gene is responsible for deciding which genes are turned on and which genes are packed tightly away,’ said Dr. Picketts. ‘Without Snf2h there to keep things organized, genes that should be packed away are left turned on, while other genes are not properly activated. This disorganization within the cell’s nucleus results in a neuron that doesn’t perform very well—like a car running on five cylinders instead of six.’

The cerebellum contains roughly half the neurons found in the brain. It also develops in response to external stimuli. So, as we practice tasks, certain genes or groups of genes are turned on and off, which strengthens these circuits and helps to stabilize or perfect the task being undertaken. The researchers found that the Snf2h gene orchestrates this complex and ongoing process. These master genes, which adapt to external cues to adjust the genes they turn on and off, are known as epigenetic regulators.

‘These epigenetic regulators are known to affect memory, behaviour and learning,’ said Dr. Picketts. ‘Without Snf2h, not enough cerebellar neurons are produced, and the ones that are produced do not respond and adapt as well to external signals. They also show a progressively disorganized gene expression profile that results in cerebellar ataxia and the premature death of the animal.’

There are no studies showing a direct link between Snf2h mutations and diseases with cerebellar ataxia, but Dr. Picketts added that it ‘is certainly possible and an interesting avenue to explore.’

In 2012, Developmental Cell published a paper by Dr. Picketts’ team showing that mice lacking the sister gene Snf2l were completely normal, but had larger brains, more cells in all areas of the brain and more actively dividing brain stem cells. The balance between Snf2l and Snf2h gene activity is necessary for controlling brain size and for establishing the proper gene expression profiles that underlie the function of neurons in different regions, including the cerebellum. Ottawa Hospital Research Institute

Two new potential therapeutic targets for the treatment of pulmonary arterial hypertension, a deadly disease marked by high blood pressure in the lungs, have been identified by researchers at the University of Illinois at Chicago.

Early symptoms of pulmonary arterial hypertension include shortness of breath and exercise intolerance. As the disease progresses, patients may require oxygen supplementation and lung transplantation. Heart failure can develop and is a major cause of death in the disease.

Most cases of pulmonary hypertension are of unknown cause, though the condition often occurs in association with other diseases, including scleroderma, congenital heart disease and liver disease. One of the underlying factors driving the increased blood pressure in the lungs is a narrowing of the pulmonary blood vessels. This narrowing can be due to an abnormal proliferation of cells within the walls of the blood vessels, particularly in the smooth muscle cells of the pulmonary artery.

Jiwang Chen, research assistant professor of critical care medicine, sleep and allergy in the UIC College of Medicine, and his colleagues investigated the molecular mechanisms behind the abnormal proliferation of smooth muscle cells in the pulmonary artery and discovered two ways that the proliferation could be suppressed.

They knew that an enzyme, sphingosine kinase 1, that produces a signalling molecule called sphingosine-1-phosphate (S1P), had been linked to the abnormal growth of cells in cancer, including lung cancer.
“The characteristic proliferation of cells that line the blood vessels in pulmonary hypertension is similar to the abnormal growth and reproduction of cells that form cancerous tumours,” says Chen. “We wanted to see if sphingosine kinase 1 and S1P were involved in the development of pulmonary arterial hypertension.”
Looking at samples of lung tissue from patients, Chen and colleagues found that patients with pulmonary arterial hypertension had significantly elevated levels of both the enzyme and the signalling molecule it produces. They found similarly elevated levels of both molecules in mouse and rat models of pulmonary hypertension.

Knockout mice lacking the gene for sphingosine kinase 1 were less likely than normal mice to develop pulmonary hypertension when exposed to the low-oxygen conditions used to induce the disease in the laboratory.

Drugs that either suppress production of sphingosine kinase 1 or block the signalling of S1P through its receptors on smooth muscle cells prevented mice from developing pulmonary hypertension in low-oxygen conditions.

The researchers also showed in mice that over-production of sphingosine kinase 1 and S1P promote the proliferation of pulmonary artery smooth muscle cells.
“Our results yield two new potential targets for the development of drugs to treat or prevent the progression of pulmonary arterial hypertension,” Chen said.
“By blocking the binding site for S1P or suppressing the production of S1P, like we did in our experimental rodent model, we can reduce the proliferation of pulmonary artery smooth muscle cells, which is a major contributor to pulmonary hypertension.” University of Illinois at Chicago

A new theory about disorders that attack the brain and spinal column has received a significant boost from scientists at Washington University School of Medicine in St. Louis.
The theory attributes these disorders to proteins that act like prions, which are copies of a normal protein that have been corrupted in ways that cause diseases. Scientists previously thought that only one particular protein could be corrupted in this fashion, but researchers in the laboratory of Marc Diamond, MD, report that another protein linked to Alzheimer’s disease and many other neurodegenerative conditions also behaves very much like a prion.
Diamond’s lab found that the protein, known as tau, could be corrupted in different ways, and that these different forms of corruption — known as strains — were linked to distinct forms of damage to the brain.
‘If we think of these different tau strains as different pathogens, then we can begin to describe many human disorders linked to tau based on the strains that underlie them,’ said senior author Diamond, the David Clayson Professor of Neurology. ‘This may mean that certain antibodies or drugs, for example, will work better against certain disorders than others.’
Prions are composed of normal proteins that have folded into an abnormal shape. They aren’t alive, but their effects can be similar to infectious microbes such as bacteria or viruses. Their unusual structure lets prions replicate themselves through a kind of molecular peer pressure: When a prion interacts with identical but normally folded proteins, it can cause these proteins to become prions, which are small aggregates, or clumps, that can spread from cell to cell.
Prions first came to popular attention in the 1990s with the emergence of mad cow disease, a disorder that destroys the brains of cattle. Scientists linked a few cases of a similar condition in people to consumption of meat from infected cows. Researchers eventually determined that the disorder was caused by a distinct strain of prions made by the sickened cattle.
Scientists had suspected that prion-like forms of a protein called alpha-synuclein contribute to Parkinson’s disease and other conditions, and prion-like versions of proteins known as SOD1 and TDP43 may cause amyotrophic lateral sclerosis, commonly known as Lou Gehrig’s disease.
Scientists also had identified tau clumps in 25 different neurodegenerative disorders, known collectively as tauopathies. This hinted at potential prion-like behaviour on the part of tau. In 2009, Diamond’s group found that tau misfolds into several different shapes in a test tube.
‘When we infected a cell with one of these misshapen copies of tau and allowed the cell to reproduce, the daughter cells contained copies of tau misfolded in the same fashion as the parent cell,’ Diamond said. ‘Further, if we extracted the tau from an affected cell, we could reintroduce it to a naïve cell, where it would recreate the same aggregate shape. This proves that each of these differently shaped copies of the tau protein can form stable prion strains, like a virus or a bacteria, that can be passed on indefinitely.’
Diamond used the tau prions made in cells to infect mouse brains, showing that differently shaped strains caused different levels of brain damage. He isolated the prions from the mice, grew them in cell culture, and then infected other mice. Throughout these transfers, each particular prion strain continued to be misfolded in the same shape and to cause damage in the same fashion.
Finally, the researchers examined clumps of tau from the brains of 28 patients after they died. Each of the patients was known to have one of five forms of tauopathy.
‘Each disease had a unique tau prion strain or combination of strains associated with it,’ he said. ‘For example, we isolated the same tau prion strain from nearly every patient with Alzheimer’s disease we examined.’
Brain samples from patients with the progressive neurological disorders corticobasal degeneration and Pick’s disease also typically had the same tau prion strains or mixtures of strains. Washington University School of Medicine

Scientists have identified a set of 10 proteins in the blood which can predict the onset of Alzheimer’s, marking a significant step towards developing a blood test for the disease.

There are currently no effective long-lasting drug treatments for Alzheimer’s, and it is believed that many new clinical trials fail because drugs are given too late in the disease process. A blood test could be used to identify patients in the early stages of memory loss for clinical trials to find drugs to halt the progression of the disease.

‘Alzheimer’s begins to affect the brain many years before patients are diagnosed with the disease,’ said Professor Simon Lovestone of the University of Oxford, who led the work while at King’s College London. ‘Many of our drug trials fail because by the time patients are given the drugs, the brain has already been too severely affected.

‘A simple blood test could help us identify patients at a much earlier stage to take part in new trials and hopefully develop treatments which could prevent the progression of the disease. The next step will be to validate our findings in further sample sets, to see if we can improve accuracy and reduce the risk of misdiagnosis, and to develop a reliable test suitable to be used by doctors.’

The study, led by King’s College London and UK proteomics company, Proteome Sciences plc, analysed over 1,000 individuals and is the largest of its kind to date.

The researchers used data from three international studies. Blood samples from a total of 1,148 individuals (476 with Alzheimer’s disease, 220 with ‘mild cognitive impairment’, and 452 elderly controls without dementia) were analysed for 26 proteins previously shown to be associated with Alzheimer’s disease. A sub-group of 476 individuals across all three groups also had an MRI brain scan.

Researchers identified 16 of these 26 proteins to be strongly associated with brain shrinkage in either mild cognitive impairment or Alzheimer’s.

They then ran a second series of tests to establish which of these proteins could predict the progression from mild cognitive impairment to Alzheimer’s. They identified a combination of 10 proteins capable of predicting whether individuals with mild cognitive impairment would develop Alzheimer’s disease within a year, with an accuracy of 87%.

Dr Abdul Hye, lead author of the study from the Institute of Psychiatry at King’s College London, said: ‘Memory problems are very common, but the challenge is identifying who is likely to develop dementia. There are thousands of proteins in the blood, and this study is the culmination of many years’ work identifying which ones are clinically relevant. We now have a set of 10 proteins that can predict whether someone with early symptoms of memory loss, or mild cognitive impairment, will develop Alzheimer’s disease within a year, with a high level of accuracy.’ Kings College London

Researchers have identified a genetic/molecular network that fuels a high-risk and aggressive form of Acute Myeloid Leukaemia (AML) and its precursor disease Myelodysplastic Syndrome (MDS) – providing a possible therapeutic strategy for an essentially untreatable form of the blood cancer.

The specific forms of AML and MDS in the current study involve deletions on the arm of a specific chromosome in blood cells (del(5q). In patients with less aggressive forms of del(5q) MDS, the percentage of bone marrow blasts in their blood (the earliest, most immature cells of the myeloid cell line) is less than 5 percent. This means treatment prognosis for those patients typically is good, according to the study’s lead investigator, Daniel Starczynowski PhD, a researcher in the division of Experimental Hematology and Cancer Biology, part of the CBDI at Cincinnati Children’s.

“Unfortunately, a large portion of del(5q) AML and MDS patients have increased number of bone marrow blasts and additional chromosomal mutations,” Starczynowski said. “These patients have very poor prognosis because the disease is very resistant to available treatments such as chemotherapy and radiation. Finding new therapies is important and this study identifies new therapeutic possibilities.”

The researchers conducted their study in human AML/MDS cells and mouse models of del(5q) AML/MDS. They found that reduced expression of a certain gene in blood cells (miR-146a) led to activation of a molecular signalling network involving several components of NF-kB, one of which involved a protein called p62 – a critical regulator of cell metabolism, cellular remodelling and certain cancers.

Deletion of the miR-146a gene led to overexpression of p62, which caused sustained activation of what researchers identified as an NF-kB signalling network. This fuelled the survival and aggressive growth of leukemic cells in cells and in mouse models.

Earlier attempts in previous studies to directly inhibit NF-kB (a key molecular facilitator to the leukemic process) have not proven successful, according to investigators on the current paper. So the authors performed follow-up laboratory tests to look for possible vulnerabilities to NF-kB and a potential workaround by targeting instead p62 within the NF-kB signalling network.
The researcher next tested inhibiting/knocking down p62 as an experimental treatment strategy in mouse models of leukaemia and in human cells.  The authors reported that targeting p62 prevented expansion of leukemic cells in mouse models and reduced the number of leukaemia cell colonies by 80 percent in human AML/MDS cells.

Starczynowski stressed that significant additional research is needed to further verify the findings and learn more about the molecular processes involved. He also cautioned that laboratory results in mouse models do not necessarily translate to humans, and it isn’t known at this time how the findings might be directly applicable to clinical treatment. Cincinnati Children’s Hospital Medical Center