Another Muscular Dystrophy Mystery Solved; MU Scientists Inch Closer to a Therapy for Patients

Approximately 250,000 people in the United States suffer from muscular dystrophy, which occurs when damaged muscle tissue is replaced with fibrous, bony or fatty tissue and loses function. Three years ago, University of Missouri scientists found a molecular compound that is vital to curing the disease, but they didn’t know how to make the compound bind to the muscle cells. In a new study, published in the Proceedings of the National Academies of Science, MU School of Medicine scientists Yi Lai and Dongsheng Duan have discovered the missing pieces to this puzzle that could ultimately lead to a therapy and, potentially, a longer lifespan for patients suffering from the disease.

Duchenne muscular dystrophy (DMD), predominantly affecting males, is the most common type of muscular dystrophy. Patients with Duchenne muscular dystrophy have a gene mutation that disrupts the production of dystrophin, a protein essential for muscle cell survival and function. Absence of dystrophin starts a chain reaction that eventually leads to muscle cell degeneration and death. While dystrophin is vital for muscle development, the protein also needs several “helpers” to maintain the muscle tissue. One of these “helper” molecular compounds is nNOS, which produces nitric oxide that can keep muscle cells healthy after exercise.

“Dystrophin not only helps build muscle cells, it’s also a key factor to attracting nNOS to the muscles cells and helping nNOS bind to the cell and help repair it following activity,” said Lai, a research assistant professor in the Department of Molecular Microbiology and Immunology. “Prior to this discovery, we didn’t know how dystrophin made nNOS bind to the cells. What we found was that dystrophin has a special ‘claw’ that is used to grab nNOS and bring it close to the muscle cell. Now that we have that key, we hope to begin the process of developing a therapy for patients.”

Genetic cause discovered for rare disorder of motor neurones

Scientists have identified an underlying genetic cause for a rare disorder of motor neurones, and believe this may help find causes of other related diseases.

Disorders of motor neurones are a group of progressive neuromuscular disorders that damage the nervous system, causing muscle weakness and wasting. These diseases affect many thousands of people in the UK. A number are inherited but the causes of the majority remain unknown, and there are no cures.

The new study has discovered a gene mutation that causes a rare disorder of motor neurones called distal hereditary motor neuropathy (dHMN). The researchers say their findings raise a possibility that mutations of the same gene or genes with similar roles might underlie other disorders of motor neurones. This could open up the potential for new treatment options, not only for dHMN but also for the wider group of these disorders.

dHMN principally affects muscles of the hands and feet, and sometimes causes a hoarse voice. Symptoms usually begin during adolescence although this can vary from infancy to the mid-thirties.

The study to investigate possible genetic causes of dHMN was led by Professor Andrew Crosby and Dr Meriel McEntagart at St George’s, University of London. It has been published in the American Journal of Human Genetics.

We all have hundreds of DNA flaws, UK geneticists say

Everyone has on average 400 flaws in their DNA, a UK study suggests. Most are “silent” mutations and do not affect health, although they can cause problems when passed to future generations. Others are linked to conditions such as cancer or heart disease, which appear in later life, say geneticists.

The evidence comes from the 1,000 Genomes project, which is mapping normal human genetic differences, from tiny changes in DNA to major mutations.

In the study, 1,000 seemingly healthy people from Europe, the Americas and East Asia had their entire genetic sequences decoded, to look at what makes people different from each other, and to help in the search for genetic links to diseases.

The new research, published in The American Journal of Human Genetics, compared the genomes of 179 participants, who were healthy at the time their DNA was sampled, with a database of human mutations developed at Cardiff University.

It revealed that a normal healthy person has on average about 400 potentially damaging DNA variations, and two DNA changes known to be associated with disease.

"Ordinary people carry disease-causing mutations without them having any obvious effect," said Dr Chris Tyler-Smith, a lead researcher on the study from the Wellcome Trust Sanger Institute, Cambridge.

He added: “In a population there will be variants that have consequences for their own health.”

The research gives an insight into the “flaws that make us all different, sometimes with different expertise and different abilities, but also different predispositions in diseases,” said Prof David Cooper of Cardiff University, the other lead researcher of the study.

Autologous mesenchymal stem cell–derived dopaminergic neurons function in parkinsonian macaques

A cell-based therapy for the replacement of dopaminergic neurons has been a long-term goal in Parkinson’s disease research. Here, we show that autologous engraftment of A9 dopaminergic neuron-like cells induced from mesenchymal stem cells (MSCs) leads to long-term survival of the cells and restoration of motor function in hemiparkinsonian macaques. Differentiated MSCs expressed markers of A9 dopaminergic neurons and released dopamine after depolarization in vitro. The differentiated autologous cells were engrafted in the affected portion of the striatum. Animals that received transplants showed modest and gradual improvements in motor behaviors. Positron emission tomography (PET) using [¹¹C]-CFT, a ligand for the dopamine transporter (DAT), revealed a dramatic increase in DAT expression, with a subsequent exponential decline over a period of 7 months. Kinetic analysis of the PET findings revealed that DAT expression remained above baseline levels for over 7 months. Immunohistochemical evaluations at 9 months consistently demonstrated the existence of cells positive for DAT and other A9 dopaminergic neuron markers in the engrafted striatum. These data suggest that transplantation of differentiated autologous MSCs may represent a safe and effective cell therapy for Parkinson’s disease.

Are You Smarter Than Your Grandfather? Probably Not.

In the mid-1980s, James Flynn made a groundbreaking discovery in human intelligence. The political scientist at the University of Otago in New Zealand found that over the last century, in every nation in the developing world where intelligence-test results are on record, IQ test scores had significantly risen from one generation to the next.

“Psychologists faced a paradox: either the people of today were far brighter than their parents or, at least in some circumstances, IQ tests were not good measures of intelligence,” writes Flynn.  

Now, in a new book, Are We Getting Smarter? Rising IQ in the Twenty-First Century, Flynn unpacks his original finding, explaining the causes for this widespread increase in IQ scores, and reveals some new ones, regarding teenagers’ vocabularies and the mental decline of the extremely bright in old age. Ultimately, Flynn concludes that human beings are not smarter—just more modern.

Malcolm Gladwell explains why the “Flynn effect,” as the trend is now called, is so surprising. “If we work in the opposite direction, the typical teenager of today, with an IQ of 100, would have grandparents with average IQs of 82—seemingly below the threshold necessary to graduate from high school,” he wrote in a New Yorker article in 2007. “And, if we go back even farther, the Flynn effect puts the average IQs of the schoolchildren of 1900 at around 70, which is to suggest, bizarrely, that a century ago the United States was populated largely by people who today would be considered mentally retarded.”

Deep inside a mouse’s ear, a swirling galaxy of cells

Is this a churning galaxy in some faraway corner of the universe? A neon rose plucked by a 1990s raver? Or just a dollop of fluorescent paint swirling down the drain? Nope - it’s the cochlea of a mouse that has been stained with antibodies to reveal cells with different functions.

The image, created by Karen Avraham and Shaked Shivatzki of Tel Aviv University in Israel, was the winning entry in the GenArt 2012 human genetics image competition.

Overlaid on the twisting cochlea is a cascade of green letters that make up the DNA sequence of connexin 26. Mutations in this gene are the most common cause for deafness, says Avraham. The image is an artistic representation of deep sequencing, a technique for detecting variances in DNA.

Avraham says deep sequencing is revolutionising the hunt for genetic mutations because of its speed and low cost. Where sequencing a genome once cost millions of dollars and took years, it now takes weeks and costs about $1000.

"By finding the mutations responsible for human disease, scientists can diagnose disorders in a way that was impossible before," she says.

New Genetic Disorder of Balance and Cognition Discovered

The family of disorders known as ataxia can impair speech, balance and coordination, and have varying levels of severity. Scientists from the Universities of Oxford and Edinburgh have identified a new member of this group of conditions which is connected to ‘Lincoln ataxia’, so called because it was first found in the relatives of US President Abraham Lincoln. The results are published in the journal PLOS Genetics.

Lincoln ataxia affects the cerebellum, a crucial part of the brain controlling movement and balance. It is caused by an alteration in the gene for ‘beta-III spectrin’, a protein found in the cerebellum. Each person has two copies of a gene, and in Lincoln ataxia there is an alteration in only one of the two copies. Unexpectedly, the British scientists have found cases of alterations in both copies of the gene, causing a novel disorder called ‘SPARCA1’ which is associated with a severe childhood ataxia and cognitive impairment.

This is the first report of any spectrin-related disorder where both copies of the gene are faulty and has given important insights into both Lincoln ataxia and SPARCA1.

The work was done using whole genome sequencing, a relatively new technology which allows all of a person’s genetics information to be analysed. In addition to sequencing work, the scientists characterized the condition using mice lacking beta-III spectrin. This analysis, combined with previous work, links the protein defect to changes in nerve-cell shape in the brain areas associated with cognition and coordinated movements. The work shows that loss of normal beta-III spectrin function underlies both SPARCA 1 and Lincoln ataxia, but a greater loss of beta-III spectrin is required before cognition problems arise.

Ultrasound Can Be Tweaked to Stimulate Different Sensations

A century after the world’s first ultrasonic detection device – invented in response to the sinking of the Titanic – Virginia Tech Carilion Research Institute scientists have provided the first neurophysiological evidence for something that researchers have long suspected: ultrasound applied to the periphery, such as the fingertips, can stimulate different sensory pathways leading to the brain.

And that’s just the tip of the iceberg. The discovery carries implications for diagnosing and treating neuropathy, which affects millions of people around the world.

“Ideally, neurologists should be able to tailor treatments to the specific sensations their patients are feeling,” said William “Jamie” Tyler, an assistant professor at the Virginia Tech Carilion Research Institute, who led the study published this week in PLOS ONE.

“Unfortunately, even with today’s technologies, it’s difficult to stimulate certain types of sensations without evoking others. Pulsed ultrasound allows us to selectively activate functional subsets of nerve fibers so we can study what happens when you stimulate, for example, only the peripheral fibers and central nervous system pathways that convey the sensation of fast, sharp pain or only those that convey the sensation of slow, dull, throbbing pain.”

Scripps Research Institute Scientists Identify Molecules in the Ear that Convert Sound into Brain Signals

For scientists who study the genetics of hearing and deafness, finding the exact genetic machinery in the inner ear that responds to sound waves and converts them into electrical impulses, the language of the brain, has been something of a holy grail.

Now this quest has come to fruition. Scientists at The Scripps Research Institute (TSRI) in La Jolla, CA, have identified a critical component of this ear-to-brain conversion—a protein called TMHS. This protein is a component of the so-called mechanotransduction channels in the ear, which convert the signals from mechanical sound waves into electrical impulses transmitted to the nervous system.

“Scientists have been trying for decades to identify the proteins that form mechanotransduction channels,” said Ulrich Mueller, PhD, a professor in the Department of Cell Biology and director of the Dorris Neuroscience Center at TSRI who led the new study, described in the December 7, 2012 issue of the journal Cell.

Not only have the scientists finally found a key protein in this process, but the work also suggests a promising new approach toward gene therapy. In the laboratory, the scientists were able to place functional TMHS into the sensory cells for sound perception of newborn deaf mice, restoring their function. “In some forms of human deafness, there may be a way to stick these genes back in and fix the cells after birth,” said Mueller.

TMHS appears to be the direct link between the spring-like mechanism in the inner ear that responds to sound and the machinery that shoots electrical signals to the brain. When the protein is missing in mice, these signals are not sent to their brains and they cannot perceive sound.

Specific genetic forms of this protein have previously been found in people with common inherited forms of deafness, and this discovery would seem to be the first explanation for how these genetic variations account for hearing loss.