New mechanism for long-term memory formation discovered

UC Irvine neurobiologists have found a novel molecular mechanism that helps trigger the formation of long-term memory. The researchers believe the discovery of this mechanism adds another piece to the puzzle in the ongoing effort to uncover the mysteries of memory and, potentially, certain intellectual disabilities.

In a study led by Marcelo Wood of UC Irvine’s Center for the Neurobiology of Learning & Memory, the team investigated the role of this mechanism – a gene designated Baf53b – in long-term memory formation. Baf53b is one of several proteins making up a molecular complex called nBAF.

Mutations in the proteins of the nBAF complex have been linked to several intellectual disorders, including Coffin-Siris syndrome, Nicolaides-Baraitser syndrome and sporadic autism. One of the key questions the researchers addressed is how mutations in components of the nBAF complex lead to cognitive impairments.

In their study, Wood and his colleagues used mice bred with mutations in Baf53b. While this genetic modification did not affect the mice’s ability to learn, it did notably inhibit long-term memories from forming and severely impaired synaptic function.

“These findings present a whole new way to look at how long-term memories form,” said Wood, associate professor of neurobiology & behavior. “They also provide a mechanism by which mutations in the proteins of the nBAF complex may underlie the development of intellectual disability disorders characterized by significant cognitive impairments.”

How does this mechanism regulate gene expression required for long-term memory formation? Most genes are tightly packaged by a chromatin structure – chromatin being what compacts DNA so that it fits inside the nucleus of a cell. That compaction mechanism represses gene expression. Baf53b, and the nBAF complex, physically open the chromatin structure so specific genes required for long-term memory formation are turned on. The mutated forms of Baf53b did not allow for this necessary gene expression.

“The results from this study reveal a powerful new mechanism that increases our understanding of how genes are regulated for memory formation,” Wood said. “Our next step is to identify the key genes the nBAF complex regulates. With that information, we can begin to understand what can go wrong in intellectual disability disorders, which paves a path toward possible therapeutics.”

Findings appear online today in Nature Neuroscience.

Mutations in VCP gene implicated in a number of neurodegenerative diseases

New research, published in Neuron, gives insight into how single mutations in the VCP gene cause a range of neurological conditions including a form of dementia called Inclusion Body Myopathy, Paget’s Disease of the Bone and Frontotemporal Dementia (IBMPFD), and the motor neuron disease Amyotrophic Lateral Sclerosis (ALS).

Single mutations in one gene rarely cause such different diseases. This study shows that these mutations disrupt energy production in cells shedding new light on the role of VCP in these multiple disorders.

In healthy cells VCP helps remove damaged mitochondria, the energy-producing engines of cells. The mutant protein can’t do this and as a result, the dysfunctional mitochondria build up.

The new study led by Dr Fernando Bartolome, Dr Helene Plun-Favreau and Dr Andrey Abramov of the UCL Institute of Neurology, found that mitochondria are damaged in cells from patients with mutant VCP. Mitochondria generate a cell’s energy, and the study found these damaged mitochondria are less efficient, burning more nutrients but producing less energy. This reduction in available energy makes cells more vulnerable, which could explain why mutations in the VCP gene lead to neurological disorders.

Lead author Dr Fernando Bartolome said, “We have found that VCP mutations are associated with mitochondrial dysfunction. VCP had previously been shown to be important in the removal of damaged mitochondria and proteins, accumulation of which is potentially very toxic to cells. A single mutation in the VCP gene could cause multiple neurological diseases because a different type of protein is accumulating in each disorder”.

In the study, the researchers used live imaging techniques to examine the functioning of mitochondria in patient cells carrying three independent VCP mutations, and in nerve cells in which the amount of VCP has been reduced.

“The next step will be to find small molecules able to correct the mitochondrial dysfunction in the VCP deficient cells”, added Dr Bartolome .

Dr Brian Dickie, the Motor Neuron Disease Association’s Director of Research Development says: “Neurons - and motor neurons in particular - are incredibly energy hungry cells. These new findings from the team at UCL show that there is a significant interruption of energy supply in this hereditary form of MND, which has strong implications for understanding the degenerative process underpinning all forms of the disease.”

Autism Speaks Through Gene Expression

Autism spectrum disorders affect nearly 1 in 88 children, with symptoms ranging from mild personality traits to severe intellectual disability and seizures. Understanding the altered genetic pathways is critical for diagnosis and treatment. New work to examine which genes are responsible for autism disorders will be presented at the 57th Annual Meeting of the Biophysical Society (BPS), held Feb. 2-6, 2013, in Philadelphia, Pa.

“Autism is the most inheritable of neurodevelopmental disorders,” explains Rajini Rao of Johns Hopkins University in Baltimore, Md., “but identifying the underlying genes is difficult since no single gene contributes more than a tiny fraction of autism cases.” Rather, she continues, “mutations in many different genes variably affect a few common pathways.”

A team of scientists at Johns Hopkins and Tel Aviv University in Israel looked at genetic variations in DNA sequence in the ion transporter NHE9 and found that autism-associated variants in NHE9 result in a profound loss of transporter function. “Altering levels of this transporter at the synapse may modulate critical proteins on the cell surface that bring in nutrients or neurotransmitters such as glutamate,” says Rao. “Elevated glutamate levels are known to trigger seizures, possibly explaining why autistic patients with mutations in these ion transporters also have seizures.”

A unique aspect of the team’s approach was that they exploited decades of basic research done in bacteria and yeast to study a complex human neurological disorder. First, the group at Tel Aviv University, led by Nir Ben-Tal, built structural models of NHE9 using a bacterial relative as a template, allowing the Rao laboratory at Johns Hopkins to use the simple baker’s yeast for screening the mutations. In the future, as genomic information becomes readily available for everyone, such easy, inexpensive, and rapid screening methods will be essential to evaluate rare genetic variants in autism and other disorders.

Rao and her team are optimistic about the potential benefits of their latest findings. “Although the research is still at an early stage, drugs that target the cellular pathways regulated by NHE9 could compensate for its loss of function and lead to potential therapy in the future,” Rao says. “These findings add a new candidate for genetic screening of at-risk patients that may lead to better diagnosis or treatment of autism.”

Discovering the Missing “LINC” to Deafness

Because half of all instances of hearing loss are linked to genetic mutations, advanced gene research is an invaluable tool for uncovering causes of deafness — and one of the biggest hopes for the development of new therapies. Now Prof. Karen Avraham of the Sackler Faculty of Medicine at Tel Aviv University has discovered a significant mutation in a LINC family protein — part of the cells of the inner ear — that could lead to new treatments for hearing disorders.

Her team of researchers, including Dr. Henning Horn and Profs. Colin Stewart and Brian Burke of the Institute of Medical Biology at A*STAR in Singapore, discovered that the mutation causes chaos in a cell’s anatomy. The cell nucleus, which contains our entire DNA, moves to the top of the cell rather than being anchored to the bottom, its normal place. Though this has little impact on the functioning of most of the body’s cells, it’s devastating for the cells responsible for hearing, explains Prof. Avraham. “The position of the nucleus is important for receiving the electrical signals that determine proper hearing,” she explains. “Without the ability to receive these signals correctly, the entire cascade of hearing fails.”

This discovery, recently reported in the Journal of Clinical Investigation, may be a starting point for the development of new therapies. In the meantime, the research could lead towards work on a drug that is able to mimic the mutated protein’s anchoring function, and restore hearing in some cases, she suggests.

Dark matter made visible before the final cut

Research findings from the University of North Carolina School of Medicine are shining a light on an important regulatory role performed by the so-called dark matter, or “junk DNA,” within each of our genes.

The new study reveals snippets of information contained in dark matter that can alter the way a gene is assembled.

“These small sequences of genetic information tell the gene how to splice, either by enhancing the splicing process or inhibiting it. The research opens the door for studying the dark matter of genes. And it helps us further understand how mutations or polymorphisms affect the functions of any gene,” said study senior author, Zefeng Wang, PhD, assistant professor of pharmacology in the UNC School of Medicine and a member of UNC Lineberger Comprehensive Cancer Center.

The study is described in a report published in the January 2013 issue of the journal Nature Structural & Molecular Biology. 

Method offers DNA blueprint of a single human cell

Humans, strawberries, honeybees, chickens and rats are among the many organisms to have their DNA sequenced. But although sequencing an individual species is challenging, it is much harder to sequence the DNA of a single cell.

To get enough DNA for sequencing, thousands or even millions of cells are usually required. And finding out which mutations are in which cells is almost impossible, and mutations present in only a few cells (like early cancerous cells) are hidden altogether.

But a technique reported today in Science provides a way to copy DNA so that more than 90% of the genome of a single cell can be sequenced. The method also makes it easier to detect minor DNA sequence variations in single cells and, so, to find genetic differences between individual cells. Such differences can help to explain how cancer becomes more malignant, how reproductive cells emerge and even how individual neurons differ.

Sunney Xie, a chemical biologist at Harvard University in Cambridge, Massachusetts, and his colleagues have developed a technique, called multiple annealing and looping-based amplification cycles (MALBAC), that allows them to sequence 93% of the genome of a human cell. In MALBAC, DNA from a single cell is isolated, then short DNA molecules called primers are added. These are complementary to random parts of the DNA, which makes them stick to the strands and act as starting points for DNA replication.

The primers consist of two parts - a sticky eight-nucleotide portion that varies and binds to the DNA, plus a common sequence of 27 nucleotides. This common sequence stops the DNA from being copied too many times and massively cuts down the amplification bias. It does this by incorporating itself into the newly copied strands so that they loop back on themselves, which prevents over-copying.

Easy Recipe

“MALBAC opens a door to many critical questions,” says Bing Ren, who studies gene regulation at the University of California, San Diego. For example, it can be used to examine how quickly mutations accumulate, and to find variations in gene-copy number and chromosomal abnormalities across a population of cells. It also helps to detects variants across more of the genome than other sequencing methods.

“I think people are going to start using it right away,” agrees James Eberwine, who works on single-cell genetics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. He adds that researchers may have to tweak conditions — such as the ratio of primers to genomic DNA — to get experiments to work.

But although MALBAC covers the genome more thoroughly than other techniques, it is not perfect. It still misses perhaps one-third of single-nucleotide variations. Also, the enzyme that copies the DNA is error prone, so the copying process itself can introduce variants that were not present in the cell.

Xie was able to weed out all false positives, but only by comparing individually sequenced genomes from three closely related cells. That will increase costs, and could prove impossible for certain tissue samples, says Nicholas Navin at the MD Anderson Cancer Center in Houston, Texas, who has developed his own techniques for single-cell sequencing.

Scientists develop scientific technique to help prevent inherited disorders in humans

A joint team of scientists from The New York Stem Cell Foundation (NYSCF) Laboratory and Columbia University Medical Center (CUMC) has developed a technique that may prevent the inheritance of mitochondrial diseases in children. The study is published online today in Nature.

Dieter Egli, PhD, and Daniel Paull, PhD, of the NYSCF Laboratory with Mark Sauer, MD, and Michio Hirano, MD, of CUMC demonstrated how the nucleus of a cell can be successfully transferred between human egg cells. This landmark achievement carries significant implications for those children who have the potential to inherit mitochondrial diseases.

Mitochondria are cellular organelles responsible for the maintenance and growth of a cell. They contain their own set of genes, passed from mother to child, and are inherited independently from the cell’s nucleus. Although mitochondrial DNA accounts for only 37 out of more than 20,000 genes in an individual, mutations to mitochondrial genes carry harmful effects.

Mitochondrial disorders, due to mutations in mitochondrial DNA, affect approximately 1 in 10,000 people, while nearly 1 in 200 individuals carries mutant mitochondrial DNA. Symptoms, manifesting most often in childhood, may lead to stunted growth, kidney disease, muscle weakness, neurological disorders, loss of vision and hearing, and respiratory problems, among others. Worldwide, a child is born with a mitochondrial disease approximately every 30 minutes, and there are currently no cures for these devastating diseases.

"Through this study, we have shown that it should be possible to prevent the inheritance of mitochondrial disorders," said Egli, PhD, co-author of the study and an Senior Researcher in the NYSCF Laboratory. "We hope that this technique can be advanced quickly toward the clinic where studies in humans can show how the use of this process could help to prevent mitochondrial disease."

Sheep Help Scientists Fight Huntington’s Disease

When University of Cambridge neurobiologist Jenny Morton began working with sheep five years ago, she anticipated docile, dull creatures. Instead she discovered that sheep are complex and curious. Morton, who studies neurodegenerative diseases such as Huntington’s, is helping evaluate sheep as new large animal models for human brain diseases.

Huntington’s is a fatal, hereditary illness that causes a cascade of cell death in the brain’s basal ganglia region. The idea to use sheep to study this disease arose in 1993 in New Zealand, a country where sheep outnumber humans seven to one. Researchers had already identified disorders shared by humans and sheep, but University of Auckland neuroscientist Richard Faull and geneticist Russell Snell had a more ambitious notion. They decided to develop a line of sheep carrying Huntington’s, which is brought on by repeats within the gene IT15, in the hopes of studying the condition’s progression and developing a treatment. They accomplished their goal in 2006 after extensive efforts.

Why sheep? For one, they have big brains—comparable to macaques, which are the only other large animals currently used to study this disease—with developed, cortical folding like our own. Also, sheep can be kept in large paddocks with their fellows and monitored remotely via data-logger backpacks, allowing scientists to study these creatures in a natural setting with fewer ethical concerns than studying caged primates. What is more, these long-lived, social animals are active and expressive, recognize faces, and have long memories. They also learn quickly and engage in experiments readily. This has allowed Morton to develop cognitive tests similar to those given to humans. The researchers can study the full progression of Huntington’s—which in humans is associated with gradual mental and motor decline—and compare the changes with the normal functioning of healthy individuals.

This spring Faull, Snell, Morton and their colleagues will begin monitoring two flocks of Huntington’s sheep in Australia. One flock will be inoculated with one of the most promising therapies yet devised—a virus that silences IT15’s mutations—and the other will serve as the control. Currently no cure exists for any human brain disease. The researchers believe these studies could be a milestone. “The tragedy of this disease is enormous. It’s a curse on the family,” Faull says. “Maybe we can lift that curse.”