Category Archives: Research News (General)

A new study has found a link between neurological birth defects in infants commonly found in pregnant women with diabetes and several neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases.

The findings were published in the Proceedings of the National Academy of Sciences.

Neural tube defects occur when misfolded proteins accumulate in the cells of the developing nervous system. The misfolded proteins form insoluble clumps and cause widespread cell death, eventually leading to birth defects. Protein clumps also play a major role in Alzheimer’s, Parkinson’s and Huntington’s disease. In Alzheimer’s, for instance, this leads to the accumulation of plaques in the brain, reducing the ability of that organ to function.

The researchers studied pregnant mice with diabetes, and found that their embryos contained clumps of at least three misfolded proteins that are also associated with the three neurodegenerative diseases: α-Synuclein, Parkin, and Huntingtin.

This latest research also underscores the links between diabetes and some neurodegenerative diseases. People with diabetes have a higher risk of Alzheimer’s and Parkinson’s disease, and some research suggests that there are molecular links between Huntington’s and diabetes as well.

The scientists also examined whether it is possible to reduce levels of the misfolded proteins, and in so doing reduce neural tube defects. They gave diabetic pregnant animals sodium 4-phenylbutyrate (PBA), a compound that can reduce mistakes in molecular structure by aiding the molecules that ensure proper protein folding. In the animals that received PBA, there was significantly less protein misfolding, and fewer neural tube defects in the embryos. PBA has already been approved by the US Food and Drug Administration for other uses, and if it proves safe and effective in humans for this purpose, it could potentially reach patients much more quickly than an entirely new drug.

Paper: “Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects”
Reprinted from materials provided by the University of Maryland School of Medicine.

A study has shown that suppressing a certain protein in a mouse model of amyotrophic lateral sclerosis (ALS) could markedly extend the animal’s life span. In one experiment, none of the untreated mice lived longer than 29 days, while some of the treated mice lived over 400 days.

This study was published in the journal Nature.

ALS is a disease in which the nerve cells in the brain and spinal cord degenerate, leading to wasting of the muscles. Patients gradually lose the ability to move, speak, eat or breathe, often leading to paralysis and death within two to five years. It is associated with environmental risk factors, such as old age and military service. In addition, mutations in certain genes can cause ALS. Exactly how ALS works is still poorly understood, but knowing which genes are involved can point researchers toward processes inside cells that would be good targets for drugs.

One indicator of ALS, as well as other neurodegenerative diseases, is clumps of protein in the brain. In ALS, these clumps, or aggregates, are made up of a protein called TDP-43. Eliminating TDP-43, and therefore the TDP-43 aggregates, might seem like a good way to prevent or cure ALS. But cells need TDP-43 to survive, so suppressing TDP-43 itself is not a good idea.

A different approach was needed. The researchers knew that a second protein, ataxin 2, helped cells survive when TDP-43 formed toxic clumps. Unlike TDP-43, ataxin 2 is not essential for a cell’s survival, making it a reasonable therapeutic target.

In a previous study, the team had shown that when ataxin 2 is suppressed or blocked in yeast cultures and fruit flies that carry the human TDP-43 gene, cells are more resistant to the potential toxic effects of the clumping TDP-43 protein.

In still another study, the scientists had shown that versions of the human ataxin 2 gene that resulted in a more stable ataxin 2 protein — and therefore more of the protein — increased the risk for developing ALS. The researchers reasoned that if mutations that increased the amount of ataxin 2 raised the risk of ALS, maybe lowering the amount of ataxin 2 would protect a person from ALS.

The scientists used genetically engineered mice whose neurons produced human TDP-43 protein at high levels. These mice exhibit some features that resemble human ALS, including a buildup of clumps of TDP-43 in their neurons. These mice also have difficulty walking and typically have life spans of no more than 30 days. They genetically engineered these ALS mice to have half the normal amount of ataxin 2, and also engineered other mice to completely lack the protein. The researchers found that with half the ataxin 2, the ALS-like mice survived much longer, and with no ataxin 2, the mice lived for hundreds of days.

The team next tried something that could have a more direct therapeutic value: treating mice with a type of DNA-like drug, designed to block the production of ataxin 2. These so called “antisense oligonucleotides” are strands of synthetic DNA that target a gene and block the expression of the protein that it encodes. Delivery of the antisense oligonucleotides to the nervous systems of some of the ALS mice enabled them to maintain their health much longer than the ALS mice treated with a placebo.

The scientists said the study showed that suppressing ataxin 2 delayed onset and slowed the progression of the ALS-like disease in mice that were not yet showing symptoms. Whether oligonucleotides or other protein-blocking treatments could reverse symptoms in mice that are already sick is another question. Because TDP-43 clumping occurs in nearly all ALS cases, targeting ataxin 2 could be a broadly effective therapeutic strategy, they say.

Paper: “Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice”
Reprinted from materials provided by Stanford University Medical Center.

A major contributor to most neurological diseases is the degeneration of a wire-like part of nerve cells called an axon, which electrically transmits information from one neuron to another. The molecular programs underlying axon degeneration are therefore important targets for therapeutic intervention — the idea being that if axons can be preserved, rather than allowed to die in diseased conditions, then loss of critical processes like movement, speech or memory will be slowed.

For more than 150 years, researchers believed that axons died independently of one another when injured as a result of trauma, such as stroke or brain injury, or of a neurological disease, such as Alzheimer’s.

But a new study challenges this idea and suggests that axons coordinate each other’s destruction, thereby contributing to the degeneration that makes neurological diseases so devastating and permanent.

The paper appears in the journal Current Biology.

The coordination described in the paper creates a ripple effect of neuron death that confounds efforts to restore the growth of healthy cells. However, the researchers also found that the death spiral can be slowed when this communication is blocked using a laboratory method that could inspire pharmacological therapies to treat pathological axon degeneration. The method demonstrates that injured axons can be preserved for at least 10 times longer when their communication with neighbors is blocked.

The researchers believe that axons communicate the death message to each other during injury as a leftover activity, “borrowed” from the nervous system’s developmental period when axons are overproduced and then improper or unnecessary connections are eliminated by similar communication between axons. While this process is essential during development, it appears to be hijacked in diseased or traumatic conditions to reactivate and accelerate neuron degeneration.

The researchers have found that axons receive the message to die as a chemical signal via a cell surface receptor known as “death receptor 6.” They speculate that this chemical signal is released from the axon itself, and they currently are working to determine the identity of this chemical signal.

Paper: “Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons”
Reprinted from materials provided by the University of Virginia.

A simple blood test may be as accurate as a spinal fluid test when trying to determine whether symptoms are caused by Parkinson’s disease or another atypical parkinsonism disorder, according to a new study published in Neurology.

In early stages of disease, it can be difficult to differentiate between Parkinson’s disease and atypical parkinsonism disorders (APDs) like multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, because symptoms can overlap. But identifying these diseases early is important because expectations concerning progression and potential benefit from treatment differ dramatically between Parkinson’s and APDs.

The study found that a nerve protein called neurofilament light chain protein can, when found in the blood, discriminate between Parkinson’s disease and APDs . It is a component of nerve cells and can be detected in the blood stream and spinal fluid when nerve cells die.

For the study, researchers examined 504 people from three study groups. Two groups, had healthy people and people who had been living with Parkinson’s or APDs for an average of four to six years. The third group was comprised of people who had been living with the diseases for three years or less. In all, there were 244 people with Parkinson’s, 88 with multiple system atrophy, 70 with progressive supranuclear palsy, 23 with corticobasal degeneration and 79 people who served as healthy controls.

Researchers found the blood test was just as accurate as a spinal fluid test at diagnosing whether someone had Parkinson’s or an APD, in both early stages of disease and in those who had been living with the diseases longer. The nerve protein levels were higher in people with APDs and lower in those with Parkinson’s disease and those who were healthy.

The researchers say that one limitation of nerve protein testing is that it does not distinguish between the different APDs, however, they note that doctors can look for other symptoms and signs to distinguish between those diseases.

Paper: “Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder”
Reprinted from materials provided by the American Academy of Neurology (AAN).

Scientists say neurodegenerative diseases like Alzheimer’s and Parkinson’s may be linked to defective brain cells disposing toxic proteins that make neighboring cells sick.

In a study published in Nature, researchers found that while healthy neurons should be able to sort out and rid brain cells of toxic proteins and damaged cell structures without causing problems, laboratory findings indicate that it does not always occur.

These findings could have major implications for neurological disease in humans and possibly be the way that disease can spread in the brain.

Scientists have understood how the process of eliminating toxic cellular substances works internally within the cell, comparing it to a garbage disposal getting rid of waste, but they did not know how cells released the garbage externally.

Working with the transparent roundworm, known as the C. elegans, which are similar in molecular form, function and genetics to those of humans, the researchers discovered that the worms — which have a lifespan of about three weeks — had an external garbage removal mechanism and were disposing these toxic proteins outside the cell as well.

The researchers found that roundworms engineered to produce human disease proteins associated with Huntington’s disease and Alzheimer’s, threw out more trash consisting of these neurodegenerative toxic materials. While neighboring cells degraded some of the material, more distant cells scavenged other portions of the diseased proteins.

Paper: “C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress”
Reprinted from materials provided by Rutgers University.

A team of researchers has identified an underlying mechanism in early onset Parkinson’s. Using flies, mice and patient cells, the team focused on cardiolipin, a fat unique to cells’ mitochondria, organelles that produce energy. They demonstrated that reducing the effects of the protein FASN influences the mitochondria, leading to increased cardiolipin levels and reduced Parkinson’s symptoms. These results could pave the way to therapies for Parkinson’s disease that target lipids. The research was published in The Journal of Cell Biology.

An estimated 10 million people are currently affected by Parkinson’s disease worldwide. A small percentage gets confronted with the disease before the age of 40. While the causes are not yet known, scientists believe that they consist of both genetic and environmental factors. In genetic Parkinson’s disease, a mutation in the PINK1 gene causes changes in neurons’ mitochondria, leading to the degeneration of these neurons.

In this study, scientists used fly, mouse and human cell models to observe that blocking a protein called FASN, which is responsible for lipid creation in cells, bypasses the genetic defect in mitochondria.

The researchers have already identified several targets for future research projects seeking greater insights into the link between the amounts of specific lipids in neurons and Parkinson’s disease.

Paper: “Cardiolipin promotes electron transport between ubiquinone and complex I to rescue PINK1 deficiency”
Reprinted from materials provided by VIB – Flanders Interuniversity Institute for Biotechnology.

An international group of researchers has identified new processes that form protein “clumps” that are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). How these proteins, which can bind RNA in normal cells, stick together has remained elusive until recently, when scientists demonstrated that they demix from the watery substance inside cells, much like oil separates from water. This latest research, featured on the cover of Molecular Cell, sheds light onto the molecular interactions behind the process in patients with defects in the C9orf72 gene.

Clumps of RNA-binding proteins occur naturally in normal neurons under times of stress in the form of stress granules (SGs), which precipitate from the water inside cells. However, in normal cells, the process of stress granule formation is tightly controlled, reversible and does not lead to disease. Scientists previously believed that hydrophobic interactions – or the protein’s inability to mix with water – caused the formation of stress granules. However, the researchers showed that in patients with defects in the C9orf72 gene, a different process can also cause this demixing, which precedes the formation of these toxic protein aggregates.

Stress granules normally behave as liquid protein droplets within a cell, while protein aggregates do not. The C9orf72 mutation causes neurons to produce small, abnormal and highly charged toxic proteins, or peptides. Yet, precisely how these peptides are toxic was not well-understood. The research team was able to observe in vitro that these peptides cause RNA-binding proteins to spontaneously stick together and change the dynamics of stress granules in cells, making them more like solids than liquids.

The scientists suggest that future research could focus on the development of a sort of ‘molecular antifreeze’ to prevent solidification and, thus, protein aggregation.

Paper: “Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics”
Reprinted from materials provided by VIB – Flanders Interuniversity Institute for Biotechnology.

For the first time a “tipping point” molecular link between the blood sugar glucose and Alzheimer’s disease has been established by scientists, who have shown that excess glucose damages a vital enzyme involved with inflammation response to the early stages of Alzheimer’s.

The study was published in Scientific Reports.

Abnormally high blood sugar levels, or hyperglycaemia, is well-known as a characteristic of diabetes and obesity, but its link to Alzheimer’s disease is less familiar.
Diabetes patients have an increased risk of developing Alzheimer’s disease compared to healthy individuals. In Alzheimer’s disease abnormal proteins aggregate to form plaques and tangles in the brain which progressively damage the brain and lead to severe cognitive decline.

Scientists already knew that glucose and its break-down products can damage proteins in cells via a reaction called glycation but the specific molecular link between glucose and Alzheimer’s was not understood.

But now scientists have unraveled that link. By studying brain samples from people with and without Alzheimer’s using a sensitive technique to detect glycation, the team discovered that in the early stages of Alzheimer’s glycation damages an enzyme called MIF (macrophage migration inhibitory factor) which plays a role in immune response and insulin regulation.

MIF is involved in the response of brain cells called glia to the build-up of abnormal proteins in the brain during Alzheimer’s disease, and the researchers believe that inhibition and reduction of MIF activity caused by glycation could be the ‘tipping point’ in disease progression. It appears that as Alzheimer’s progresses, glycation of these enzymes increases.

Paper: “Macrophage Migration Inhibitory Factor is subjected to glucose modification and oxidation in Alzheimer’s Disease”
Reprinted from materials provided by University of Bath.

A gene variant that produces red hair and fair skin in humans and in mice, which increases the risk of the dangerous skin cancer melanoma, may also contribute to the known association between melanoma and Parkinson’s disease. Reseachers report that mice carrying the red hair variant of the melanocortin 1 receptor (MC1R) gene have reduced production of the neurotransmitter dopamine in the substantia nigra — the brain structure in which dopamine-producing neurons are destroyed in Parkinson’s disease (PD) — and are more susceptible to toxins known to damage those neurons.

This work was published in Annals of Neurology. Inherited variants of the MC1R gene determine skin pigmentation, with the most common form leading to greater production of the darker pigment called eumelanin and the red-hair-associated variant, which inactivates the gene’s function, increasing production of the lighter pigment called pheomelanin. Not only does pheomelanin provide less protection from ultraviolet damage to the skin than does eumelanin, but a previous study found it also may directly contribute to melanoma development.

While patients with Parkinson’s disease have a reduced risk of developing most types of cancer, their higher-than-expected risk of melanoma is well recognized, as is the increased risk of PD in patients with melanoma.

The team’s experiments showed that, in mice with the common form of MC1R, the gene is expressed in dopamine-producing neurons in the substantia nigra. The red-haired mice in which the gene is inactivated because of a mutation were found to have fewer dopamine-producing neurons and as they aged developed a progressive decline in movement and a drop in dopamine levels. They also were more sensitive to toxic substances known to damage dopamine-producing neurons and had indications of increased oxidative stress in brain structures adjacent to the substantia nigra. Treatment with a substance that increases MC1R signaling reduced the susceptibility of mice with the common variant to a neurotoxin, further supporting a protective role for the gene’s activity.

Paper: “The melanoma-linked ‘redhead’ MC1R influences dopaminergic neuron survival”
Reprinted from materials provided by Massachusetts General Hospital.

Abnormality with special cells that wrap around blood vessels in the brain leads to neuron deterioration, possibly affecting the development of Alzheimer’s disease, a new study reveals.

“Gatekeeper cells” called pericytes surround blood vessels, contracting and dilating to control blood flow to active parts of the brain.

Published in Nature Neuroscience, this was the first study to use a pericyte-deficient mouse model to test how blood flow is regulated in the brain. The goal was to identify whether pericytes could be an important new therapeutic target for treating neuron deterioration.

Pericyte dysfunction suffocates the brain, leading to metabolic stress, accelerated neuronal damage and neuron loss, the researchers say. To test the theory, they stimulated the hind limb of young mice deficient in gatekeeper cells and monitored the global and individual responses of brain capillaries, the smallest blood vessels in the brain. The global cerebral blood flow response to an electric stimulus was reduced by about 30 percent compared to normal mice, denoting a weakened system.

Relative to the control group, the capillaries of pericyte-deficient mice took 6.5 seconds longer to dilate. Slower capillary widening and a slower flow of red blood cells carrying oxygen through capillaries means it takes longer for the brain to get its fuel.

As the mice turned 6 to 8 months old, global cerebral blood flow responses to stimuli progressively worsened. Blood flow responses for the experimental group were 58 percent lower than that of their age-matched peers. In short, with age, the brain’s malfunctioning vascular system exponentially worsens.

The researchers say that their study brings new information to the study of Alzheimer’s disease and ALS. Previous studies have shown that pericytes die in Alzheimer’s and ALS patients, and this study demonstrated that the death of these pericytes restricts blood flow and oxygen to the brain. The next step, they say, will be to try to reveal what kills pericytes in Alzheimer’s and ALS in the first place.

Paper: “Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain”
Reprinted from materials provided by University of Southern California.