Scientists are a step closer to understanding how some of the brain’s 100 billion nerve cells co-ordinate their communication.

The University of Bristol research team investigated some of the chemical processes that underpin how brain cells co-ordinate their communication. Defects in this communication are associated with disorders such as epilepsy, autism and schizophrenia, and therefore these findings could lead to the development of novel neurological therapies.

Neurons in the brain communicate with each other using chemicals called neurotransmitters. This release of neurotransmitter from neurons is tightly controlled by many different proteins inside the neuron. These proteins interact with each other to ensure that neurotransmitter is only released when necessary. Although the mechanisms that control this release have been extensively studied, the processes that co-ordinate how and when the component proteins interact is not fully understood.

The School of Biochemistry researchers have now discovered that one of these proteins called ‘RIM1α’ is modified by a small protein named ‘SUMO’ which attaches to a specific region in RIM1α. This process acts as a ‘molecular switch’ which is required for normal neurotransmitter release.

Jeremy Henley, Professor of Molecular Neuroscience in the University’s Faculty of Medical and Veterinary Sciences and the study’s lead author, said: ‘These findings are important as they show that SUMO modification plays a vital and previously unsuspected role in normal brain function.’ Bristol University

It has been estimated that 3 to 4 million people are infected with hepatitis C virus (HCV) each year with the risk of developing liver cirrhosis and/or liver cancer. More than 350,000 people die each year from HCV-related conditions. With earlier detection and diagnosis, patients have a hope of receiving timely treatment and care for improved management of the condition. MP Biomedicals recently obtained the CE Marking for its patented multiparameter HCV test, the Multisure HCV antibody test. This test is intended for the detection and differentiation of Hepatitis C antibodies that may be present in patients with acute or chronic HCV infection. This innovative test is based on the patented reverse-flow technology, giving greater sensitivity and stronger visual signals. Multisure HCV uses human whole blood, plasma or serum. The test is fast and can help differentiate HCV antibodies against both structural and non-structural proteins across six genotypes.

For the first time, large-scale information on the biochemical makeup of small interfering RNA (siRNA) molecules is available publicly. These molecules are used in research to help scientists better understand how genes function in disease. Making these data accessible to researchers worldwide increases the potential of finding new treatments for patients.
NIH’s National Center for Advancing Translational Sciences (NCATS) collaborated with Life Technologies Corporation of Carlsbad, Calif., which owns the siRNA information, to make it available to all researchers.
RNA interference(RNAi), a cellular process that can stop specific proteins from being coded by silencing the genes that produce them.
The siRNA molecules, which can selectively inhibit the activity of genes, are used in RNA interference (RNAi) research. RNAi is a natural process that cells use to control the activity of specific genes. Its discovery led to the 2006 Nobel Prize in Physiology or Medicine.
Last month, a team of NIH scientists, led by Richard Youle, Ph.D., at the National Institute of Neurological Disorders and Stroke (NINDS), and Scott Martin, Ph.D., at NCATS, used RNAi to find genes that linked to Parkinson’s disease, a devastating movement disorder. The new genes may represent new starting points for developing treatments.
Scientists have harnessed the power of RNAi to study the function of many individual genes by reducing their activity levels, or silencing them. This process enables researchers to identify genes and molecules that are linked to particular diseases. To do this, researchers use siRNAs, which are RNA molecules that have a complementary chemical makeup, or sequence, to that of a targeted gene. While the gene is silenced, researchers look for changes in cell functions to gain insights about what it normally does. By silencing genes in the cell one at a time, scientists can explore and understand their complex relation to other genes in the context of disease.
Until now, a major limitation in the scientific community’s use of RNAi data has been the lack of a publicly available dataset, along with siRNA sequences directed against every human gene. Historically, providers have not allowed publishing of proprietary siRNA sequence information. To address this problem, NCATS and Life Technologies are providing all researchers with access to siRNA data from Life Technologies’ Silencer Select siRNA library, which includes 65,000 siRNA sequences targeting more than 20,000 human genes. Simultaneously, NCATS is releasing complementary data on the effects of each siRNA molecule on biological functions. All of this information is available to the public free-of-charge through NIH’s public database PubChem.
‘Producing and releasing these data demonstrate NCATS’ commitment to speeding the translational process for all diseases,’ said NCATS Director Christopher P. Austin, M.D. ‘The Human Genome Project showed that public data release is critical to scientific progress. Similarly, I believe that making RNAi data publicly available will revolutionise the study of biology and medicine.’
Experts from the NIH RNAi initiative, administered by NCATS’ Division of Pre-Clinical Innovation, conduct screens for NIH investigators. They will add new RNAi data into PubChem on an ongoing basis, making the database a growing resource for gene function studies.
‘By releasing all our siRNA sequences, we are enabling novel strategies to advance fundamental understanding of biology and discovery of new potential drug targets,’ said Mark Stevenson, president and chief operating officer of Life Technologies.
NIH invites other companies that sell siRNA libraries and researchers who conduct genome-wide RNAi screens with the Life Technologies library to deposit sequence data and biological activity information into PubChem. For assistance with submitting data to PubChem, researchers may contact info@ncbi.nlm.nih.gov.
‘Translation of siRNA library screening results into impactful downstream experiments is the ultimate goal of scientists using our library,’ said Alan Sachs, M.D., Ph.D., head of global research and development for Life Technologies. ‘The availability of these sequence data should greatly facilitate this effort because scientists no longer will be blinded to the actual sequence they are targeting.’ National Institutes of Health

A study done by researchers at Fox Chase Cancer Center shows that many relatives of patients who undergo testing for a gene linked to breast and ovarian cancers misinterpret the results, and less than half of those who could benefit from genetic testing say they plan to get tested themselves—despite the fact that knowing your genetic status may help catch the disease in its earliest stages.
‘People don’t always understand genetic information, so there’s confusion,’ says study author Mary B. Daly, MD, PhD, chair of the Department of Clinical Genetics at Fox Chase. ‘Family members are either not understanding what they’re hearing, not realising it has implications for them, or they’re not hearing it at all.’
For a long time, Daly says she ‘naively’ assumed that, once one family member knew whether or not they carried genes linked to breast and ovarian cancers—known as BRCA1/2—their entire family would understand the result, and what it meant for their own genetic risk. ‘Over time, we realised that wasn’t happening, or it wasn’t happening very well.’
Some genetic information is straightforward, says Daly. For example, when a woman learns she carries BRCA1/2 that means her parents, siblings and children may also carry the gene. But there are more ‘indeterminate’ results, which are harder to interpret, she adds. If a woman with a strong family history of breast and ovarian cancers tests negative for the BRCA1/2 genes, that does not mean her relatives are not at risk, says Daly—her siblings could still carry the gene, or there could be additional genes present that predispose them to cancer that clinicians don’t yet know how to test for.
‘When you look at some of these families who are so full of breast and ovarian cancer, and the person tests negative, you think there’s got to be something going on here. We just can’t find it. That’s a difficult thing for someone to explain to a relative,’ says Daly.
To understand better what was (and was not) being communicated after people underwent genetic testing, Daly and her team called 438 relatives of 253 people who had undergone genetic testing and said they’d shared their results. More than one-quarter of family members reported the test result incorrectly. They were most likely to understand positive results—like their family member carries the BRCA1/2 gene. But only 60% understood the so-called ‘indeterminate’ results, where their relative tested negative for the gene but they and other family members could still be at risk. Nearly one-third said they had trouble understanding the result.
Concerningly, only half (52%) of family members whose relative tested positive for the BRCA1/2 gene said they planned to get tested themselves. Among those whose relative tested negative for the BRCA1/2 gene, but knew the gene was present in their families (meaning they could still carry the gene), only 36% said they were going to find out their own genetic risk. ‘These findings imply the family members did not fully understand the significance of these results for their own risk,’ says Daly.
People were more likely to share their results with adult children than parents or siblings, and particularly with female relatives. ‘Over and over you hear people say ‘I’m doing this for my children’s sake,” says Daly.
As part of the study, Daly and her colleagues had asked half of the people getting tested to participate in two coaching sessions to help them communicate their results to relatives, such as through role playing. However, these people were no more likely to communicate the result of their tests than people who had simply sat through educational sessions about overall health. ‘It didn’t matter which group they were in, unfortunately,’ says Daly. ‘That disappointed me.’
But it also inspired her to develop the next project—exploring the effect of directly reaching out to the relatives of someone who underwent genetic testing (with that person’s permission), to see if hearing the results from an expert who’s not personally involved in the situation helps family members understand what they mean. Fox Chase Cancer Center

St. Jude Children’s Research Hospital scientists led a study showing that mutations in a gene responsible for amyotrophic lateral sclerosis (ALS) disrupt the RNA transport system in nerve cells.
The findings offer a new avenue for researchers to pursue in the quest for desperately needed treatments for ALS, a disorder that kills most patients within five years of diagnosis. ALS, also known as Lou Gehrig’s disease, is diagnosed in about 5,600 individuals nationwide each year and is associated with muscle weakness and paralysis.
The gene, TDP-43, carries instructions for making a protein of the same name. While mutations in TDP-43 were known to cause ALS and a related neurodegenerative disorder, until now the mechanism involved was a mystery. This study showed for the first time that the mutations disrupt efficient movement within nerve cells of RNA molecules. These RNA molecules direct protein assembly based on instructions carried in DNA. Correct transport of these RNAs permits proteins to be made in the right place at the right time.
Working in motor neurons derived from patients with ALS, researchers demonstrated that each of three different TDP-43 mutations impaired delivery of RNA molecules to their final destination near the junction where a nerve and its target muscle meet. Without the RNA molecules, nerves cannot make proteins necessary to function normally and respond quickly when stimulated. Motor neurons govern movement, including breathing. Their death and deterioration is a hallmark of ALS.
The results also provide insight into how problems in RNA metabolism, including disturbances in RNA regulation and functioning, lead to ALS and other neurodegenerative diseases.
‘Five years of tremendous progress in ALS genetics has revealed that RNA metabolism is a critical pathway that is impaired in this disease,’ said the study’s corresponding author J. Paul Taylor, M.D., Ph.D., a member of the St. Jude Department of Developmental Neurobiology. ‘But RNA metabolism is a complex process that involves multiple steps that are carried out in different parts of the cell. This study provides a more refined understanding of how ALS-causing mutations impair RNA metabolism so we know what needs fixing therapeutically.’
TDP-43 belongs to a family of proteins that bind to RNA and regulate its function. Normally TDP-43 is stored in the cell’s command center, the nucleus. There the protein prepares DNA for translation into the proteins that do the work of cells and shuttles the resulting RNA, called mRNA, from the nucleus to the cytoplasm, the cell’s liquid center. While clumps of TDP-43 were known to accumulate in the cytoplasm of the motor neurons of patients with ALS and other neurodegenerative diseases, the protein’s function there was unknown.
This study provides an answer. The work was done in motor neurons from the fruit fly Drosophila melanogaster, mouse brain cells and human motor neurons produced by reprogramming cells from ALS patients with three different TDP-43 mutations. Co-first author Nael Alami, Ph.D., a postdoctoral fellow in Taylor’s laboratory, developed a florescent RNA beacon that let investigators track movement of RNA molecules in living cells.
Researchers demonstrated that TDP-43 is part of a molecule called an RNA transport granule. These granules are responsible for moving mRNA efficiently to the end of the axon where the molecule is translated into a protein. For this study, scientists used Neurofilament-L (NEFL) mRNA, which is known to bind TDP-43.
In human motor neurons growing in the laboratory, investigators found that transport granules with mutant TDP-43 were more likely than granules with unaltered TDP-43 to stall en route to the nerve ending and sometimes reverse direction. The defect in the human ALS motor neurons was apparent after the first week.
Evidence from mice suggests TDP-43 mutations selectively rather than globally disrupt movement in nerve cells. The mutations did not affect movement of another cell structure, the mitochondria, along the axon where mRNA movement was impaired.
‘We know neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases, seem to share a common mechanism,’ Alami said. ‘We plan to use our finding from this study to look for similar defects in those diseases.’ St. Jude Children’s Research Hospital