“Criteria for folding in structure-based models of proteins” has been published in The Journal of Chemical Physics. This research was supported in part by JPND through the MisingLink project, selected in the 2013 cross-disease analysis call.
A paper titled “Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy” has been published in The American Journal of Human Genetics. This research was supported in part by JPND through the COURAGE-PD project, selected in the 2012 risk factors call.
A new paper titled “Structural and functional properties of prefibrillar α-synuclein oligomers” has been published in Scientific Reports. It was partly funded by JPND through the NeuTARGETs project, which was selected for support in the 2013 call for research projects for cross-disease analysis of pathways related to neurodegenerative diseases.
Because billions of neurons are packed into our brain, the neuronal circuits that are responsible for controlling our behaviors are by necessity highly intermingled. This tangled web makes it complicated for scientists to determine exactly which circuits do what. Now, researchers have mapped out the pathways of a set of neurons responsible for the kinds of motor impairments—such as difficulty walking—found in patients with Parkinson’s disease.
The work was published in the journal Neuron.
In patients with Parkinson’s disease, gait disorders and difficulty with balance are often caused by the degeneration of a specific type of neuron—called cholinergic neurons—in a region of the brainstem called the pedunculopontine nucleus (PPN). Damage to this same population of neurons in the PPN is also linked to reward-based behaviors and disorders, such as addiction.
Previously, researchers had not been able to untangle the neural circuitry originating in the PPN to understand how both addictions and Parkinson’s motor impairments are modulated within the same population of cells. Furthermore, this uncertainty created a barrier to treating those motor symptoms. After all, deep brain stimulation—in which a device is inserted into the brain to deliver electrical pulses to a targeted region—can be used to correct walking and balance difficulties in these patients, but without knowing exactly which part of the PPN to target, the procedure can lead to mixed results.
“The circuits responsible for controlling our behaviors are not nicely lined up, where this side does locomotion and this side does reward,” says the leader of the study, Viviana Gradinaru, and this disordered arrangement arises from the way neurons are structured. Much as a tree extends into the ground with long roots, neurons are made up of a cell body and a long string-like axon that can diverge and project elsewhere into different areas of the brain. Because of this shape, the researchers realized they could follow the neuron’s “roots” to an area of the brain less crowded than the PPN. This would allow them to more easily look at the two very different behaviors and how they are implemented.
Cheng Xiao, the first author on the study, began by mapping the projections of the cholinergic neurons in the PPN of a rat using a technique developed by the Gradinaru lab called Passive CLARITY Technique, or PACT. In this technique, a solution of chemicals is applied to the brain; the chemicals dissolve the lipids in the tissue and render that region of the brain optically transparent—see-through, in other words—and able to take up fluorescent markers that can label different types of neurons. The researchers could then follow the path of the PPN neurons of interest, marked by a fluorescent protein, by simply looking through the rest of the brain.
Using this method, Gradinaru and Xiao were able to trace the axons of the PPN neurons as they extended into two regions of the midbrain: the ventral substantia nigra, a landmark area for Parkinson’s disease that had been previously associated with locomotion; and the ventral tegmental area, a region of the brain that had been previously associated with reward.
Next, the researchers used an electrical recording technique to keep track of the signals sent by PPN neurons—confirming that these neurons do, in fact, communicate with their associated downstream structures in the midbrain. Then, the scientists went on to determine how this specific population of neurons affects behavior. To do this, they used a technique that Gradinaru helped develop called optogenetics, which allows researchers to manipulate neural activities—in this case, by either exciting or inhibiting the PPN neural projections in the midbrain—using different colors of light.
Using the optogenetic approach in rats, the researchers found that exciting the neuronal projections in the ventral substantia nigra would stimulate the animal to walk around its environment; by contrast, they could stop the animal’s movement by inhibiting these same projections. Furthermore, they found that they could stimulate reward-seeking behavior by exciting the neuronal projections in the ventral tegmental area, but could cause aversive behavior by inhibiting these projections.
“Our results show that the cholinergic neurons from the PPN indeed have a role in controlling both behaviors,” Gradinaru says. “Although the neurons are very densely packed and intermingled, these pathways are, to some extent, dedicated to very specialized behaviors.” Determining which pathways are associated with which behaviors might also improve future treatments, she adds.
“In the past it’s been difficult to target treatment to the PPN because the specific neurons associated with different behaviors are intermingled at the source—the PPN. Our results show that you could target the axonal projections in the substantia nigra for movement disorders and projections in the ventral tegmental area for reward disorders, as addiction is,” Gradinaru says. In addition, she notes, these projections in the midbrain are much easier to access surgically than their source in the PPN.
Although this new information could inform clinical treatments for Parkinson’s disease, the PPN is only one region of the brain and there are many more important examples of connectivity that need to be explored, Gradinaru says. “These results highlight the need for brain-wide functional and anatomical maps of these long-range neuronal projections; we’ve shown that tissue clearing and optogenetics are enabling technologies in the creation of these maps.”
Source: Reprinted from materials provided by Caltech.
The Lancet Neurology Conference: Preclinical neurodegenerative disease — towards prevention and early diagnosis is now accepting abstracts for poster presentation at its 2016 meeting, which will take place October 19-21, 2016, in London, UK.
Abstracts can be submitted on the following topics:
- Genetic factors, cellular pathways, and neuronal vulnerability
- Environmental factors, epidemiology, and primary prevention
- Biomarkers and early diagnosis
- Prevention through therapeutics
- Trials; regulatory and ethical considerations
The deadline to submit is June 3, 2016. For more information, visit The Lancet Neurology Conference website.
Researchers have used a non-invasive method of observing how the process leading to Parkinson’s disease takes place at the nanoscale, and identified the point in the process at which proteins in the brain become toxic, eventually leading to the death of brain cells.
The results suggest that the same protein can either cause, or protect against, the toxic effects that lead to the death of brain cells, depending on the specific structural form it takes, and that toxic effects take hold when there is an imbalance of the level of protein in its natural form in a cell. The work could help unravel how and why people develop Parkinson’s, and aid in the search for potential treatments. The study is published in the journal Proceedings of the National Academy of Sciences.
Using super-resolution microscopy, researchers were able to observe the behaviour of different types of alpha-synuclein, a protein closely associated with Parkinson’s disease, in order to find how it affects neurons, and at what point it becomes toxic.
Parkinson’s disease is one of a number of neurodegenerative diseases caused when naturally occurring proteins fold into the wrong shape and stick together with other proteins, eventually forming thin filament-like structures called amyloid fibrils. These amyloid deposits of aggregated alpha-synuclein, also known as Lewy bodies, are the hallmark of Parkinson’s disease.
Parkinson’s disease is the second-most common neurodegenerative disease worldwide (after Alzheimer’s disease). More than seven million people worldwide have the disease. Symptoms include muscle tremors, stiffness and difficulty walking. Dementia is common in later stages of the disease.
The researchers used different forms of alpha-synuclein and observed their behaviour in neurons from rats. They were then able to correlate what they saw with the amount of toxicity that was present.
They found that when they added alpha-synuclein fibrils to the neurons, they interacted with alpha-synuclein protein that was already in the cell, and no toxic effects were present.
The researchers then observed that by adding the soluble form of alpha-synuclein together with amyloid fibrils, the toxic effect of the former could be overcome. It appeared that the amyloid fibrils acted like magnets for the soluble protein and mopped up the soluble protein pool, shielding against the associated toxic effects.
The research shows how important it is to fully understand the processes at work behind neurodegenerative diseases, so that the right step in the process can be targeted.
Source: Adapted from materials provided by the University of Cambridge
“Nanoscopic insights into seeding mechanisms and toxicity of α-synuclein species in neurons”
Researchers are studying the causes of premature ageing of neurons in Parkinson’s patients with a defective DJ1 (PARK7) gene. The genetic defect causes changes in the cellular metabolism meaning that neurons are subjected to oxidative stress and an increased immune response in the brain. The study has just been published in the scientific journal Neurobiology of Disease.
Parkinson’s disease, the second most common neurodegenerative disease, has genetic causes in 15% of cases. Premature ageing of dopaminergic neurons in the substantia nigra in the brain is the reason for the motor symptoms that characterise this disease. However, how this happens is not yet fully understood.
In the current study, researchers looking for the answer in metabolism investigated a specific form of Parkinson’s disease with a defective DJ1 gene and discovered that two key metabolic pathways are affected.
The research team was also able to show that mutations in the DJ1 gene can also negatively affect other cells in the brain. Microglial cells, which are responsible for the immune reaction in the brain, become ‘hyperactive’ when the DJ1 gene is defective.
Interestingly, the researchers were able to determine metabolic changes not only in the brain’s immune cells but also in the blood of Parkinson’s patients with mutant DJ1. This could lead to new diagnostic avenues in the future.
The next step will involve investigating how affected metabolic pathways can be influenced using drugs. The changes described in glutamine and serine metabolic processes could thus be used to develop novel approaches for treating Parkinson’s.
Source: University of Luxembourg
Scientists have developed a new optical technique to study how information is transmitted in the brains of mice. Using this method, they found that only a small portion of synapses — the connections between cells that control brain activity — may be active at any given time.
The study was published in the latest issue of Nature Neuroscience.
To obtain a detailed view of synaptic activity, the researchers developed a novel compound called fluorescent false neurotransmitter 200 (FFN200). When added to brain tissue or nerve cells from mice, FFN200 mimics the brain’s natural neurotransmitters and allows researchers to spy on chemical messaging in action.
Using a fluorescence microscope, the researchers were able to view the release and reuptake of dopamine — a neurotransmitter involved in motor learning, habit formation, and reward-seeking behavior — in individual synapses. When all the neurons were electrically stimulated in a sample of brain tissue, the researchers expected all the synapses to release dopamine. Instead, they found that less than 20 percent of dopaminergic synapses were active following a pulse of electricity.
“This particular study didn’t explain what’s causing most of the synapses to remain silent,” said David Sulzer, a co-author of the paper. “If we can work this out, we may learn a lot more about how alterations in dopamine levels are involved in brain disorders such as Parkinson’s disease, addiction, and schizophrenia.”
Source: Columbia University Medical Center
An innovative tool allows researchers to observe protein aggregation throughout the life of a worm. The development of these aggregates, which play a role in the onset of a number of neurodegenerative diseases, can now be monitored automatically and in real time. This breakthrough was made possible by isolating worms in tiny microfluidic chambers.
Biologists and microfluidics specialists have joined forces and developed a highly innovative research tool: a 2cm by 2cm ‘chip’ with 32 independent compartments, each of which is designed to hold a nematode – a widely used worm in the research world. The device is described in the journal Molecular Neurodegeneration.
Each of these ‘cells’ is fed by microfluidic channels. These allow variable concentrations of nutrients or therapeutic molecules to be injected with precision. The ambient temperature can also be adjusted. Each worm is observed through a microscope throughout its life. However, for more detailed investigations and very high resolution images, the worms need to be immobilized.
This method is fully reversible and does not affect the nematode’s development. Using it, researchers can observe the formation of protein aggregates linked to several neurodegenerative diseases like Alzheimer’s, Parkinson’s and Huntington’s. The same worm can be photographed several times, as the clusters develop.
Nematodes are very useful models for studying a number of human diseases. In many cases, they obviate the need to experiment on rodents. But until now, handling nematodes was a delicate affair. By simplifying the process, this new technology should accelerate research on numerous afflictions and how they are treated.
Source: Emmanuel Barraud, École polytechnique fédérale de Lausanne
A study published in Scientific Reports demonstrates, for the first time and using computational tools, that polyunsaturated lipids can alter the binding rate of two types of receivers involved in certain nervous system diseases.
Using latest-generation molecular simulations, which are like “computational microscopes,” the researchers have demonstrated that a decrease in polyunsaturated lipids in neuronal membranes, as seen in Parkinson’s and Alzheimer’s sufferers, directly affects the binding rate of dopamine and adenosine receptors. These are part of the family of receptors connected to the G protein (GPCR), located in the cell membrane and responsible for transmitting signals to within the cell. Various studies have demonstrated that lipid profiles in the brains of people with diseases like Alzheimer’s and Parkinson’s are very different from those of healthy people. These studies showed that the levels of a polyunsaturated fatty acid in neuronal membranes are considerably lower in the brains of sufferers. The researchers believe that this difference in the lipid composition of membranes could alter the way in which certain proteins interact with each other, as in the case of the GPCR receivers.
These results could enable, in the future, new therapeutic pathways to be initiated for regulating the binding of these receivers, either through the lipid composition of the membrane or by designing new lipids that have a modulating effect on this binding rate. It could also facilitate the study of other similar scenarios where specific membrane lipids are able to modulate the behaviour of other important receivers, at a clinical level.
Source: Hospital del Mar Medical Research Institute