Deep inside the brains of people with dementia and Lou Gehrig’s disease, globs of abnormal protein gum up the inner workings of brain cells – dooming them to an early death.

But boosting those cells’ natural ability to clean up those clogs might hold the key to better treatment for such conditions.

That’s the key finding of new research from a University of Michigan Medical School physician scientist and his colleagues in California and the United Kingdom. They reported their latest findings this week in the journal Nature Chemical Biology.

Though the team showed the effect worked in animals and human neurons from stem cells, not patients, their discoveries point the way to find new medicines that boost the protein-clearing cleanup process.

The work also shows how an innovative microscope technique can help researchers see what’s going on inside brain cells, as they labor to clear out the protein buildup.

The researchers focused on a crucial cell-cleaning process called autophagy – a hot topic in basic medical research these days, as scientists discover its important role in many conditions. In autophagy, cells bundle unwanted materials up, break them down and push the waste products out.

In the newly published research, the team showed how the self-cleaning capacity of some brain cells gets overwhelmed if the cells make too much of an abnormal protein called TDP43. They found that cells vary greatly in how quickly their autophagy capacity gets swamped.

In brain cells that were made from stem cells derived from ALS patients, treatment with two drugs that stimulate autophagy led to longer cell survival (middle two lines).

But they also showed how three drugs that boost autophagy – speeding up the clean-out process – could keep the brain cells alive longer.

Longer-living, TDP43-clearing brain cells are theoretically what people with Lou Gehrig’s disease (amyotrophic lateral sclerosis or ALS) and certain forms of dementia (called frontotemporal) need. But only further research will show for sure.

Sami Barmada, M.D., Ph.D., the U-M neurologist and scientist who is first author of the new study, says the new findings are encouraging – and so is the success of a microscope technique used in the research. His new lab, in the U-M Department of Neurology, is continuing to refine ways to view the inner workings of nerve cells.

“Using this new visualization technique, we could truly see how the protein was being cleared, and therefore which compounds could enhance the pace of clearance and shorten the half-life of TDP43 inside cells,” he says. “This allowed us to see that increased autophagy was directly related to improved cell survival.”

Barmada worked on the team at the Gladstone Institutes and the University of California San Francisco headed by Steven Finkbeiner, M.D., Ph.D., that published the new findings. The team used stem cells derived from the cells of people who have ALS to grow neurons and astrocytes – the two types of brain cell most crucial to normal brain function.

Because he both sees patients in clinic and studies neurological disease in the laboratory, Barmada brings a special perspective to the research.

At U-M, he specializes in treating patients who have neurological diseases that affect both thinking and muscle control. About a third of ALS patients develop signs of frontotemporal dementia, also called FTD – and about 10 percent of people with FTD also have a motor neuron disease that affects their brain’s ability to control muscle movement. 

One of the drugs tested in the study, an antipsychotic drug developed in the 1960s to treat people with schizophrenia, had actually shown some anti-dementia promise in human ALS patients, but comes with many side effects. Barmada notes that Finkbeiner’s team at the Gladstone Institute is already working to identify other compounds that could produce the effect with fewer side effects.

Interestingly, small studies have suggested that people with schizophrenia who take antipsychotic drugs are much less likely to develop ALS.

Barmada’s work at U-M now focuses on the connection between brain cells’ ability to clear abnormal proteins. He also studies the cells’ regulation of RNA molecules created as part of expressing protein-encoding genes. Looking further upstream in the protein-producing process could yield further clues to why disease develops and what can be done about it, he says.

(Source: uofmhealth.org)

An international team of researchers identified a pathogenic mechanism that is common to several neurodegenerative diseases. The findings suggest that it may be possible to slow the progression of dementia even after the onset of symptoms.

The relentless increase in the incidence of dementia in aging societies poses an enormous challenge to health-care systems. An international team of researchers led by Professor Christian Haass and Gernot Kleinberger at the LMU‘s Adolf-Butenandt-Institute and the German Center for Neurodegenerative Diseases (DZNE), has now elucidated the mode of action of a genetic defect that contributes to the development of several different dementia syndromes.

Neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases or frontotemporal dementia display a number of common features. They are all characterized by the appearance in the brains of affected patients of abnormally high levels of insoluble protein deposits, which are associated with massive loss of nerve cells. In order to minimize further damage to nerve cells in the vicinity of such deposits, dead cells and the proteinaceous aggregates released from them must be efficiently degraded and disposed of. This task is performed by specialized phagocytic cells – the so-called microglia – which act as “sanitary inspectors” in the brain to ensure the prompt removal of debris that presents a danger to the health of nearby cells. Microglia are found only in the central nervous system, but functionally they represent a division of the body’s innate immune system.

As Haass and his colleagues now report in the latest issue of the journal Science Translational Medicine, specific mutations in the gene for a protein called TREM2, which regulates the uptake of waste products by microglia, lead to its absence from the cell surface. TREM2 is normally inserted into the plasma membrane of microglial cells such that part of it extends through the membrane as an extracellular domain. This exposed portion of TREM2 is responsible for the recognition of waste products left behind by dead cells. “We believe that the genetic defect disrupts the folding of the protein chain soon during its synthesis in the cell, so that it is degraded before it can reach the surface of the microglia,” says Kleinberger. As a result, the amount of debris that the microglia can cope with is significantly reduced. Consequently, the toxic protein deposits, as well as whole dead cells, cannot be efficiently removed and continue to accumulate in the brain. This is expected to trigger inflammatory reactions that may promote further nerve-cell loss.

The new study thus pinpoints a mechanism that influences the course of several different brain diseases. “In addition, our findings may perhaps point to ways of slowing the rate of progression of these illnesses even after the manifestation of overt signs of dementia, which has not been possible so far,” says Haass. “That this may indeed be feasible is suggested by the initial results of an experiment in which we were able to stimulate the phagocytic activity of microglia by pharmacological means.”

(Source: en.uni-muenchen.de)

Men born in November, December or January are more likely of being left-handed than during the rest of the year. While the genetic bases of handedness are still under debate, scientists at the Faculty of Psychology, University of Vienna, obtained indirect evidence of a hormonal mechanism promoting left-handedness among men. Psychologist Ulrich Tran and his colleagues published their findings in the scientific journal “Cortex”.

Various manual tasks in everyday life require the use of the right hand or are optimized for right-handers. Around 90 percent of the general population is right-handed, only about 10 percent is left-handed. The study of Ulrich Tran, Stefan Stieger, and Martin Voracek comprised two large and independent samples of nearly 13000 adults from Austria and Germany. As in modern genetic studies, where a discovery-and-replication-sample design is standard, the use of two samples allowed testing the replicability and robustness of findings within one-and-the-same study. Overall, 7.5 percent of women and 8.8 percent of men were left-handed. “We were surprised to see that this imbalance was caused by more left-handed men being born specifically during November, December, and January. On a monthly average, 8.2 percent of left-handed men were born during the period February to October. During November to January, this number rose to 10.5 percent”, according to Ulrich Tran, lead author of the study.

A hormonal cause during embryonic development
"Presumably, the relative darkness during the period November to January is not directly connected to this birth seasonality of handedness. We assume that the relative brightness during the period May to July, half a year before, is its distal cause", explains Ulrich Tran. A theory, brought forth in the 1980s by US neurologists Norman Geschwind and Albert Galaburda, posits that testosterone delays the maturation of the left brain hemisphere during embryonic development. The left brain hemisphere is dominant among right-handers, the right brain hemisphere is dominant among left-handers. Intrauterine testosterone levels are higher in the male fetus, because of its own testosterone secretion, than in the female fetus. However, the testosterone level of the mother and external factors may also affect intrauterine testosterone levels. Specifically, more daylight may increase testosterone levels, making a seasonality effect plausible.

Previous studies on the subject provided mixed and inconsistent evidence. There was no clear indication which season has an effect, and whether seasonality affects men, women or both sexes equally. According to the current findings, there is a small, but robust and replicable, effect of birth seasonality on handedness, affecting only men. These results are consistent with a hormonal basis of handedness, corroborating thus an old and controversial theory. However, the exact way of causation needs to be investigated in future studies.

(Source: medienportal.univie.ac.at)

Johns Hopkins researchers have begun to connect the dots between a schizophrenia-linked genetic variation and its effect on the developing brain. As they report July 3 in the journal Cell Stem Cell, their experiments show that the loss of a particular gene alters the skeletons of developing brain cells, which in turn disrupts the orderly layers those cells would normally form.

(Image caption: Left, human neural stem cells form rosettes as they grow into different cell types, with ringlike patterns of PKCλ protein in the center. A neural rosette with a 15q11.2 microdeletion, a risk factor for schizophrenia, appears disorganized and lacks the ringlike PKCλ protein structure, right, suggesting that this risk factor acts early in the neurodevelopmental process. Credit: Ki-Jun Yoon/Johns Hopkins Medicine)

“This is an important step toward understanding what physically happens in the developing brain that puts people at risk of schizophrenia,” says Guo-li Ming, M.D., Ph.D., a professor of neurology and neuroscience in the Johns Hopkins University School of Medicine’s Institute for Cell Engineering.

While no single genetic mutation is known to cause schizophrenia, so-called genome wide association studies have identified variations that are more common in people with the condition than in the general population. One of these is a missing piece from an area of the genome labeled 15q11.2. “While the deletion is linked to schizophrenia, having extra copies of this part of the genome raises the risk of autism,” notes Ming.

For the new study, Ming’s research group, along with that of her husband and collaborator, neurology and neuroscience professor Hongjun Song, Ph.D., used skin cells from people with schizophrenia who were missing part of 15q11.2 on one of their chromosomes. (Because everyone carries two copies of their genome, the patients each had an intact copy of 15q11.2 as well.)

The researchers grew the human skin cells in a dish and coaxed them to become induced pluripotent stem cells, and then to form neural progenitor cells, a kind of stem cell found in the developing brain.

“Normally, neural progenitors will form orderly rings when grown in a dish, but those with the deletion didn’t,” Ming says. To find out which of the four known genes in the missing piece of the genome were responsible for the change, the researchers engineered groups of progenitors that each produced less protein than normal from one of the suspect genes. The crucial ingredient in ring formation turned out to be a gene called CYFIP1.

The team then altered the genomes of neural progenitors in mouse embryos so that they made less of the protein created by CYFIP1. The brain cells of the fetal mice turned out to have similar defects in structure to those in the dish-grown human cells. The reason, the team found, is that CYFIP1 plays a role in building the skeleton that gives shape to each cell, and its loss affects spots called adherens junctions where the skeletons of two neighboring cells connect.

Having less CYFIP1 protein also caused some neurons in the developing mice to end up in the wrong layer within the brain. “During development, new neurons get in place by ‘climbing’ the tendrils of neural progenitor cells,” Ming says. “We think that disrupted adherens junctions don’t provide a stable enough anchor for neural progenitors, so the ‘rope’ they form doesn’t quite get new neurons to the right place.”

The researchers say they also found that CYFIP1 is part of a complex of proteins called WAVE, which is key to building the cellular skeleton.

Many people with a CYFIP1 deletion do not get schizophrenia, so the team suspected the condition was more likely to arise in people with a second defect in the WAVE complex.

Analyzing data from genomewide association studies, they found a variation in the WAVE complex signaling gene ACTR2/Arp2 that, combined with the CYFIP1 deletion, increased the risk of schizophrenia more than either genetic change by itself.

In adding to science’s understanding of schizophrenia, the study also shows how other mental illnesses might be similarly investigated, the researchers say. “Using induced pluripotent stem cells from people with schizophrenia allowed us to see how their genes affected brain development,” says Song. “Next, we’d like to investigate what effects remain in the mature brain.”

(Source: hopkinsmedicine.org)