The absence of a protein called SMG1 could be a contributing factor in the development of Parkinson’s disease and other related neurological disorders, according to a study led by the Translational Genomics Research Institute (TGen).

The study screened 711 human kinases (key regulators of cellular functions) and 206 phosphatases (key regulators of metabolic processes) to determine which might have the greatest relationship to the aggregation of a protein known as alpha-synuclein, which has been previously implicated in Parkinson’s disease. Previous studies have shown that hyperphosphorylation of the α-synuclein protein on serine 129 is related to this aggregation.

‘Identifying the kinases and phosphates that regulate this critical phosphorylation event may ultimately prove beneficial in the development of new drugs that could prevent synuclein dysfunction and toxicity in Parkinson’s disease and other synucleinopathies,’ said Dr. Travis Dunckley, a TGen Assistant Professor and senior author of the study.

Synucleinopathies are neurodegenerative disorders characterised
by aggregates of α-synuclein protein. They include Parkinson’s, various forms of dementia and multiple systems atrophy (MSA).

By using the latest in genomic technologies, Dr. Dunckley and collaborators found that expression of the protein SMG1 was ‘significantly reduced’ in tissue samples of patients with Parkinson’s and dementia.

‘These results suggest that reduced SMG1 expression may be a contributor to α-synuclein pathology in these diseases,’ Dr. Dunckley said.

TGen collaborators in this study included researchers from Banner Sun Health Institute and Mayo Clinic Scottsdale. Translational Genomics Research Institute

Studying epithelial cells, the cell type that most commonly turns cancerous, Johns Hopkins researchers have identified a protein that causes cells to release from their neighbours and migrate away from healthy mammary, or breast, tissue in mice. They also found that deletion of a cellular ‘Velcro protein’ does not cause the single-celled migration expected. Their results, they say, help clarify the molecular changes required for cancer cells to metastasize.

Because epithelial cells give rise to 85 percent of all cancers, the work may have implications outside of breast cancer.

Epithelial cells line the inside and outside of organs throughout the body. The team focused their work on mammary epithelial cells, which form the ducts that carry milk within the breast. ‘Tumour cells have to break their connections to other epithelial cells in order to leave the breast and build metastases in other parts of the body,’ explains Andrew Ewald, Ph.D., assistant professor of cell biology and oncology at the Johns Hopkins University School of Medicine.

For their study, Ewald’s team removed small pieces of mammary tissue from normal mice and grew them in gels that mimic their natural environment. By using coloured proteins to mark different types of cells, they were able to use microscopes to watch how cell behaviour varied with the genetics of the cells.

The first protein they studied was E-cadherin, which is found on the surface of most epithelial cells and is used to connect epithelial cells to each other. E-cadherin is like the Velcro that holds epithelial cells together, and its absence is often associated with human breast cancers, says Ewald.

In one experiment, the team deleted the protein from normal mouse mammary cells and watched what happened. Expecting the cells to completely disconnect and move out on their own into the surrounding gel, the researchers were surprised to find that most of the epithelial cells remained connected to each other, although their organisation was disrupted. Some of the epithelial cells did penetrate the gel, but usually in single-file ‘columns’ that remained connected to the tissue. A similar result was seen in live mice.

‘For tumour cells to metastasise, they have to begin interacting with the proteins outside of the tumour and eventually strike out on their own,’ says Eliah Shamir, a graduate student in Ewald’s lab and lead author on the study. ‘When we deleted E-cadherin, the epithelial cells began interacting more with proteins in the gel, but they didn’t lose contact with the rest of the mammary tissue.’

In a second set of experiments, the team turned on a gene called Twist1, which is thought to affect the activity of many genes needed to transform groups of stationary epithelial cells into independent, mobile cells. The result, they say, was dramatic. Within 24 hours of turning on Twist1, dozens of individual cells began to move past the epithelial boundary and into the gel beyond. Again, similar results were seen when the experiment was repeated in live mice.

Surprisingly, the researchers say that when they caused epithelial cells lacking E-cadherin to turn on Twist1, the cells were no longer able to escape into the gel as single cells. Instead, they created many ‘columns’ of cells, which didn’t detach from the mammary tissue. These results suggest that the single-celled detachment and migration induced by Twist1 actually requires the presence of E-cadherin — the Velcro protein that helps bind the cells together. ‘This finding is quite counterintuitive,’ Ewald says, ‘and we are eager to understand the biology behind it.’

Since Twist1 is known to affect the activity of many genes, the researchers have begun to narrow down which of those genes is responsible for the cellular spread they witnessed. With that information, they hope to identify new means of preventing metastasis.

‘Our goal is to improve outcomes for patients with metastatic breast cancer, and this work takes us one step closer to doing so,’ says Ewald. John Hopkin’s Medicine

Researchers at the RIKEN Center for Life Science Technologies, in collaboration with Osaka City University and Kansai University of Welfare Sciences, have used functional PET imaging to show that levels of neuroinflammation, or inflammation of the nervous system, are higher in patients with chronic fatigue syndrome than in healthy people.

Chronic fatigue syndrome, which is also known as myalgic encephalomyelitis, is a debilitating condition characterised by chronic, profound, and disabling fatigue. Unfortunately, the causes are not well understood.
Neuroinflammation—the inflammation of nerve cells—has been hypothesised to be a cause of the condition, but no clear evidence has been put forth to support this idea. Now, in this clinically important study, the researchers found that indeed the levels of neuroinflammation markers are elevated in CFS/ME patients compared to the healthy controls.
The researchers performed PET scanning on nine people diagnosed with CFS/ME and ten healthy people, and asked them to complete a questionnaire describing their levels of fatigue, cognitive impairment, pain, and depression. For the PET scan they used a protein that is expressed by microglia and astrocyte cells, which are known to be active in neuroinflammation.

The researchers found that neuroinflammation is higher in CFS/ME patients than in healthy people. They also found that inflammation in certain areas of the brain—the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons—was elevated in a way that correlated with the symptoms, so that for instance, patients who reported impaired cognition tended to demonstrate neuroinflammation in the amygdala, which is known to be involved in cognition. This provides clear evidence of the association between neuroinflammation and the symptoms experienced by patients with CFS/ME.
Though the study was a small one, confirmation of the concept that PET scanning could be used as an objective test for CFS/ME could lead to better diagnosis and ultimately to the development of new therapies to provide relief to the many people around the world afflicted by this condition. Dr. Yasuyoshi Watanabe, who led the study at RIKEN, stated, ‘We plan to continue research following this exciting discovery in order to develop objective tests for CFS/ME and ultimately ways to cure and prevent this debilitating disease.’ RIKEN

A team of researchers from UCLA and Harvard University have demonstrated a technique that, by measuring the physical properties of individual cells in body fluids, can diagnose cancer with a high degree of accuracy.
The technique, which uses a deformability cytometer to analyse individual cells, could reduce the need for more cumbersome diagnostic procedures and the associated costs, while improving accuracy over current methods. The initial clinical study analysed pleural fluid samples from more than 100 patients.
Pleural fluid, a natural lubricant of the lungs as they expand and contract during breathing, is normally present in spaces surrounding the lungs. Medical conditions such as pneumonia, congestive heart failure and cancer can cause an abnormally large buildup of the fluid, which is called a pleural effusion.
When cytopathologists screen for cancer in pleural effusions, they perform a visual analysis of prepared cells extracted from the fluid. Preparing cells for this analysis can involve complicated and time-consuming dyeing or molecular labelling, and the tests often do not definitively determine the presence of tumour cells. As a result, additional costly tests often are required.
The method in the UCLA–Harvard study, developed previously by the UCLA researchers, requires little sample preparation, relying instead on the imaging of cells as they flow through in microscale fluid conduits.
Imagine squeezing two balloons, one filled with water and one filled with honey. The balloons would feel different and would deform differently in your grip. The researchers used this principle on the cellular level by using a fluid grip to ‘squeeze’ individual cells that are 10,000 times smaller than balloons—a technique called ‘deformability cytometry.’ The amount of a cell’s compression can provide insights about the cell’s makeup or structure, such as the elasticity of its membrane or the resistance to flow of the DNA or proteins inside it. Cancer cells have a different architecture and are softer than healthy cells and, as a result, ‘deform’ differently.
Using deformability cytometry, researchers can analyse more than 1,000 cells per second as they are suspended in a flowing fluid, providing significantly more detail on the variations within each patient’s sample than could be detected using previous physical analysis techniques.
The researchers also noted that the more detailed information they obtained improved the sensitivity of the test: Some patient samples that were not identified as cancerous via traditional methods were found to be so through deformability cytometry. These results were verified six months later.

‘Building off of these results, we are starting studies with many more patients to determine if this could be a cost-effective diagnostic tool and provide even more detailed information about cancer origin,’ said Dino Di Carlo, associate professor of bioengineering at the UCLA Henry Samueli School of Engineering and Applied Science and a co-principal investigator on the research. ‘It could help to reduce laboratory workload and accelerate diagnosis, as well as offer doctors a new way to improve clinical decision-making.’ University of California – Los Angeles

For the first time, scientists at King’s College London have identified a gene linking the thickness of the grey matter in the brain to intelligence. The study may help scientists understand biological mechanisms behind some forms of intellectual impairment.
The researchers looked at the cerebral cortex, the outermost layer of the human brain. It is known as ‘grey matter’ and plays a key role in memory, attention, perceptual awareness, thought, language and consciousness. Previous studies have shown that the thickness of the cerebral cortex, or ‘cortical thickness’, closely correlates with intellectual ability, however no genes had yet been identified.
An international team of scientists, led by King’s, analysed DNA samples and MRI scans from 1,583 healthy 14 year old teenagers, part of the IMAGEN cohort. The teenagers also underwent a series of tests to determine their verbal and non-verbal intelligence.
Dr Sylvane Desrivières, from the MRC Social, Genetic and Developmental Psychiatry Centre at King’s College London’s Institute of Psychiatry and lead author of the study, said: ‘We wanted to find out how structural differences in the brain relate to differences in intellectual ability. The genetic variation we identified is linked to synaptic plasticity – how neurons communicate. This may help us understand what happens at a neuronal level in certain forms of intellectual impairments, where the ability of the neurons to communicate effectively is somehow compromised.’
She adds: ‘It’s important to point out that intelligence is influenced by many genetic and environmental factors. The gene we identified only explains a tiny proportion of the differences in intellectual ability, so it’s by no means a ‘gene for intelligence’.’
The researchers looked at over 54,000 genetic variants possibly involved in brain development. They found that, on average, teenagers carrying a particular gene variant had a thinner cortex in the left cerebral hemisphere, particularly in the frontal and temporal lobes, and performed less well on tests for intellectual ability. The genetic variation affects the expression of the NPTN gene, which encodes a protein acting at neuronal synapses and therefore affects how brain cells communicate.
To confirm their findings, the researchers studied the NPTN gene in mouse and human brain cells. The researchers found that the NPTN gene had a different activity in the left and right hemispheres of the brain, which may cause the left hemisphere to be more sensitive to the effects of NPTN mutations. Their findings suggest that some differences in intellectual abilities can result from the decreased function of the NPTN gene in particular regions of the left brain hemisphere.
The genetic variation identified in this study only accounts for an estimated 0.5% of the total variation in intelligence. However, the findings may have important implications for the understanding of biological mechanisms underlying several psychiatric disorders, such as schizophrenia, autism, where impaired cognitive ability is a key feature of the disorder.
Paper reference: Desrivières, S. et al. ‘Single nucleotide polymorphism in the neuroplastin locus associates with cortical thickness and intellectual ability in adolescents’ published in Molecular Psychiatry King’s College London