Genetic defect may cause rare movement disorders

A Massachusetts General Hospital (MGH)-led research team has found that a defect in transcription of the TAF1 gene may be the cause of X-linked dystonia parkinsonism (XDP), a rare and severe neurodegenerative disease. Symptoms begin around age 40 with dystonia-involuntary muscle contractions that can force the body into abnormal, sometimes twisted positions and eventually proceed to Parkinson's-like symptoms, such as slowness of movement and a shuffling gait. Patients become progressively more disabled as the disease progresses and often die from complications such as infections or pneumonia.

Individuals with XDP share seven DNA sequence changes, which cluster within a region of the X-chromosome that includes the TAF1 gene. These sequence changes have always appeared to be inherited together. The largest genomics study ever performed for XDP, analyzing a total of 792 DNA samples from individuals with XDP and their unaffected relatives, as well as historical samples from studies dating back to the initial descriptions of the disease.

The analysis of these samples revealed a far greater genetic diversity among XDP patients than was previously known. While most shared a total of 54 unique sequence changes in a collection of variants known as a haplotype, in some individuals the haplotype had been broken apart due to genetic recombination. By comparing these recombination events, it was possible to narrow the disease-causing genomic segment to a smaller region that contained only the TAF1 gene.

Researchers reprogramed skin cells from patients with XDP and their healthy relatives back into stem cells, which differentiated into neural progenitor cells and then mature neurons. The team used RNA sequencing to characterize TAF1 expression patterns and found a defect in how the DNA sequence is transcribed into RNA in neural cells from XDP patients. In those cells, a portion of the TAF1 RNA appeared to terminate prematurely, which reduced expression of the full-length RNA. The truncated TAF1 RNA ended close to a known XDP-specific sequence variants - a large DNA insertion known as a retrotransposon.

 To determine whether the retrotransposon caused the transcriptional defect, t used genome they used editing tools to remove the sequence, which restored RNA transcription and normalized TAF1 expression. In a separate study, they analyzed the sequence of the retrotransposon in patients with XDP and found that it contained a segment of repetitive DNA that was longer in patients who developed symptoms at an earlier age and shorter in those whose symptoms appeared later.
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How gene shaped human face

Researchers from KU Leuven (Belgium) and the universities of Pittsburgh, Stanford, and Penn State (US) have identified fifteen genes that determine human facial features. Human DNA determines what an individual look like, including facial features. That appeals to the popular imagination, as the potential applications are obvious. Doctors could use DNA for skull and facial reconstructive surgery, forensic examiners could sketch a perpetrator's face on the basis of DNA retrieved from a crime scene, and historians would be able to reconstruct facial features using DNA from days long gone.

In a new study conducted by KU Leuven in collaboration with the universities of Pittsburgh, Stanford and Penn State, the researchers adopted a different approach. "Our search doesn't focus on specific traits," lead author Peter Claes (KU Leuven) explains. "My colleagues from Pittsburgh and Penn State each provided a database with 3D images of faces and the corresponding DNA of these people. Each face was automatically subdivided into smaller modules. Next, we examined whether any locations in the DNA matched these modules. This modular division technique made it possible for the first time to check for an unprecedented number of facial features."

The scientists were able to identify fifteen locations in human DNA. The Stanford team found out that genomic loci linked to these modular facial features are active when human face develops in the womb. "Furthermore, we also discovered that different genetic variants identified in the study are associated with regions of the genome that influence when, where and how much genes are expressed," says Joanna Wysocka (Stanford). Seven of the fifteen identified genes are linked to the nose, and that's good news, Peter Claes (KU Leuven) continues. "

A skull doesn't contain any traces of the nose, which only consists of soft tissue and cartilage. Therefore, when forensic scientists want to reconstruct a face on the basis of a skull, the nose is the main obstacle. If the skull also yields DNA, it would become much easier to determine the shape of the nose. Age, environment, and lifestyle have an impact on what human face looks like, this could provide genetic insight into the shape and functioning of human brain, as well as in neurodegenerative diseases such as Alzheimer's."
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Calcium may cause Parkinson's disease

The international team, led by the University of Cambridge, found that calcium can mediate the interaction between small membranous structures inside nerve endings, which are important for neuronal signalling in the brain, and alpha-synuclein, the protein associated with Parkinson's disease. Excess levels of either calcium or alpha-synuclein may be what starts the chain reaction that leads to the death of brain cells.

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 sign of Parkinson's disease.

Curiously, it hasn't been clear until now what alpha-synuclein actually does in the cell: why it's there and what it's meant to do. It is implicated in various processes, such as the smooth flow of chemical signals in the brain and the movement of molecules in and out of nerve endings, but exactly how it behaves is unclear.

"Alpha-synuclein is a very small protein with very little structure, and it needs to interact with other proteins or structures in order to become functional, which has made it difficult to study," said senior author Dr Gabriele Kaminski Schierle from Cambridge's Department of Chemical Engineering and Biotechnology.

Super-resolution microscopy techniques makes it possible to look inside cells to observe the behaviour of alpha-synuclein. To do so, researchers isolated synaptic vesicles, part of the nerve cells that store the neurotransmitters which send signals from one nerve cell to another.

In neurons, calcium plays a role in the release of neurotransmitters. The researchers observed that when calcium levels in the nerve cell increase, such as upon neuronal signalling, the alpha-synuclein binds to synaptic vesicles at multiple points causing the vesicles to come together. This may indicate that the normal role of alpha-synuclein is to help the chemical transmission of information across nerve cells.

There is a fine balance of calcium and alpha-synuclein in the cell, and when there is too much of one or the other, the balance is tipped and aggregation begins, leading to Parkinson's disease. The imbalance can be caused by a genetic doubling of the amount of alpha-synuclein (gene duplication), by an age-related slowing of the breakdown of excess protein, by an increased level of calcium in neurons that are sensitive to Parkinson's, or an associated lack of calcium buffering capacity in these neurons.

Understanding the role of alpha-synuclein in physiological or pathological processes may aid in the development of new treatments for Parkinson's disease. One possibility is that drug candidates developed to block calcium, for use in heart disease for instance, might also have potential against Parkinson's disease.
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How to live longer

Many cells in human body, such as those which make up brain need to last a lifetime. To do this human cells have developed ways of protecting themselves. One way is through a process called autophagy, which literally means self-eating, where damaged components are collected together and removed from the cell.This is very important as accumulation of damage in cells has been linked to several diseases including dementia.

Lead author, Dr Viktor Korolchuk explains: "As we age, we accumulate damage in our cells and so it is thought that activating autophagy could help us treat older people suffering from dementia. In order to be able to do this we need to understand how we can induce this cell cleaning." In this study the authors were able to identify how a protein called p62 is activated to induce autophagy. They found that p62 can be activated by reactive oxygen species (ROS). ROS are by-products of our metabolism that can cause damage in the cell.

This ability of p62 to sense ROS allows the cell to remove the damage and to survive this stress. In lower organisms, such as fruit flies, p62 is not able to do this. The team identified the part of the human p62 protein which allows it to sense ROS and created genetically modified fruit flies with 'humanised' p62. These 'humanised' flies survived longer in conditions of stress. Abilities like sensing stress and activating protective processes like autophagy may have evolved to allow better stress resistance and a longer lifespan.

Specific mutations in human p62, which cause a neurodegenerative disease called amyotrophic lateral sclerosis (ALS), can prevent activation of p62 by ROS. These cells are then unable to induce protective autophagy, and the authors explain that this could underlie the premature death of neurons in patients with this devastating age-related disease. In contrast, 'humanised' p62 fruit flies did not live longer suggesting that other mechanisms may be required. The research demonstrates that a collection of small adaptations like that of human p62 could have accumulated over time and these adaptations could underlie our increased natural defences and longer lifespans. The discovery of these adaptations allows a better understanding of how to treat age-related diseases.
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Urea in the brain causes dementia

 The build-up of urea in the brain to toxic levels can cause brain damage - and eventually dementia. Metabolic linkages between Huntington's, other neurodegenerative diseases and type-2 diabetes. Huntington's Disease - one of seven major types of age-related dementia - is directly linked to brain urea levels and metabolic processes. Urea is similarly linked to Alzheimer's disease.

The Huntington's study also showed that the high urea levels occurred before dementia sets in, which could help doctors to one day diagnose and even treat dementia, well in advance of its onset. Urea and ammonia in the brain are metabolic breakdown products of protein. Urea is more commonly known as a compound which is excreted from the body in urine. If urea and ammonia build up in the body because the kidneys are unable to eliminate them, for example, serious symptoms can result.

Alzheimer's and Huntington's are at opposite ends of the dementia spectrum. Dementia results in a progressive and irreversible loss of nerve cells and brain functioning, causing loss of memory and cognitive impairments affecting the ability to learn. Currently, there is no cure.

The team used human brains, donated by families for medical research, using cutting-edge gas chromatography mass spectrometry to measure brain urea levels. For levels to be toxic urea must rise 4-fold or higher than in the normal brain. Treating this metabolic state in the brain may help in the regeneration of tissue that can reverse dementia.
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Memory depends on subtle brain signals

The fragrance of hot pumpkin pie can bring back pleasant memories of holidays past, while the scent of an antiseptic hospital room may cause a shudder. The power of odors to activate memories both pleasing and aversive exists in many animals. The intricate biochemical mechanism for storing scent-associated memories differs slightly from a less-understood mechanism for erasing unnecessary memories.

Understanding how brains actively erase memories may open new understanding of memory loss and aging, and open the possibility of new treatments for neurodegenerative disease. In multiple ways, the processes of forgetting and remembering are alike. In fruit fly models of odor-associated learning, both the saving and erasure of memories involves
dopamine activation of the brain cells. This clue in flies is important for understanding the human brain.

The olfactory systems of flies and humans are actually quite similar in terms of neuron types and their connections.activation of the neurons causes them to make an identical messenger molecule,  Tcyclic AMP, leading to a cascade of activity within the cell, either building or breaking down memory storage.

The research team discovered one G protein, called G alpha S, that latched on to a neural dopamine receptor called dDA1, associated with memory formation. They found a different G protein, called G alpha Q, linked up with a nearby dopamine receptor called Damb, associated with the machinery of forgetting. The next question was whether those two different G proteins could be controllers of the fly brain's memory machinery.

To find out, the researchers silenced genes involved in the production of the G alpha Q protein in the flies. The flies with the protein silenced were exposed to odors in aversive situations and sent through mazes to see how well they remembered to turn away in the presence of the scent. It appears in flies that some level of forgetting is a constant, healthy process.

There is a slow process that whittles away memories, and it continues whittling them away unless another part of the brain signals the memory is important and overrides it.It may be that the process of acquiring and forgetting memories ebbs and flows in a state of balance. Important memories like the taste of mom's pumpkin pie might be forever retained, but trivialities like what you wore ten years ago can fade into oblivion without consequence.
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Immune cells can repair damaged nerves

Immune cells fight infections, in a new study, scientists have discovered how they also help the nervous system remove debris, clearing the way for nerve regeneration after injury. Some immune cells- neutrophils can clean up nerve debris. Neutrophils are one of the most common types of immune cells and known to engulf microorganisms, but they are not associated with peripheral nerve damage caused by diabetes or trauma.

Damaged nerve cells produce a stream of molecular lures that specifically attract neutrophils to injury sites in mice. Damaged mouse sciatic nerves produced hundreds of times the normal amount of two "chemoattractant" molecules, Cxcl1 and Cxcl2, which attach to the surfaces of neutrophils and draw the immune cells into injured tissue.

Once at the injury site, the neutrophils engulf cellular debris caused by the nerve damage, tidying up the area so the cells can repair themselves. Without the cellular clearance mechanism, nerves can't properly regenerate after injury. The experiments included sorting immune cells found at injury sites by molecules on their cellular surfaces, and many hours looking at mouse cells through the microscope.

Several different cells pick up the slack in the absence of macrophages, it was the neutrophil that emerged as a major contributor to debris removal. We also discovered that when we depleted neutrophils, nerve debris clearance was significantly halted in both normal mice and mice lacking a major population of macrophages.

Without neutrophils, nerve cells could not properly clear debris. This could leads to new therapeutics designed to repair nerve cells damaged by neurodegenerative disease. The clearance of debris after an injury is necessary for effective nerve regeneration. Immunostimulant molecules that target neutrophils at nerve injury location might enhance clean-up and promote nerve cell repair. Immunostimulant molecules are used to treat chronic infections and immunodeficiency.
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Third-hand smoke exposure affects liver and kidney

Third-hand smoke exposure can damage brain, liver, increase the risk of neurodegenerative diseases, and destroy metabolism. The research team analyzed how people were affected by inhaling smoke from smoker's clothes, hair, home, or car.

Being a third-hand smoker for one month can cause type 2 diabetes, hyperactivity, liver and lung damage, and wound-healing complications.
Exposure for two months resulted in further molecular damage, and at four to six months caused more damage, long-term exposure can leads to insulin resistance.

Researchers discovered that stress hormones, such as epinephrine, increased in one month of exposure.
Additional stress hormones are seen at two months, four months, and six months, eventually leading to immune fatigue.

Contaminants can be absorbed through the skin and through breathing. Exposure to tobacco smoke deposited on surfaces in homes and dust is a new form of toxicity. Noxious chemicals in tobacco smoke once deposited change in chemistry to become even more toxic and carcinogenic.
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