Yearly Archives: 2017

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.