Yearly Archives: 2017

By inserting an amyotrophic lateral sclerosis (ALS)-linked human gene called TDP-43 into fruit flies, researchers have discovered a potential role for ‘transposons’ in the disease. Transposons, which are also called ‘jumping genes’ because they jump from place to place within DNA, are virus-like entities that fill most of the spaces between genes in an organism. The new research demonstrates that these transposons are no longer effectively inhibited, resulting in a storm of jumping genes, leading to DNA damage accumulation and cell death. The research, published in PLOS Genetics, may be a clue to the genetic processes of ALS and the idea that anti-transposon systems may collapse in individuals with ALS.

Transposon replication has evolved to the point where almost half of human DNA consists of these jumping gene sequences. But our cells have developed a highly effective immune-like system to stifle the replication of these moving genes in a vast majority of instances. The researchers conducted experiments using transgenic fruit flies and discovered that anti-transposon systems appear to collapse in brains of fruit flies that contain the ALS linked human gene.

In the study, the researchers engineered the fruit flies to contain TDP-43. Just like humans, this gene caused the fruit flies to experience a progressive loss of movement and premature death. Studying the brains of the fruit flies, the team found that not only were certain transposons not inhibited and triggered a storm of the jumping genes, but one fly transposon called ‘gypsy’ appeared to be the lead culprit of the problem. By deactivating gypsy, cell death stopped and the lifespan of the mutant flies improved.

Humans do not have the gypsy transposon but do have a similar one called HERV-K. Previous research has revealed some ALS patients post-mortem had elevated levels of HERV-K.

The next step for the research team is to determine whether jumping genes are similarly activated in ALS patient tissue, and to determine whether they contribute to disease progression.

Paper “Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS”
Reprinted from materials provided by Stony Brook University.

Donepezil, a medication that is approved to treat people with Alzheimer’s disease, should not be prescribed for people with mild cognitive impairment without a genetic test, according to a new study published in the Journal of Alzheimer’s Disease. Researchers discovered that for people who carry a specific genetic variation — the K-variant of butyrylcholinesterase, or BChE-K — donezpezil could accelerate cognitive decline.

Mild cognitive impairment is a transitional state between normal age-related changes in cognition and dementia. Because many people with the condition display symptoms similar to those caused by Alzheimer’s disease, some physicians prescribe donepezil, which is the most-prescribed medication for Alzheimer’s.

Donepezil was tested as a possible treatment for mild cognitive impairment in a large, federally funded American study but was not approved. Still, doctors have often prescribed the drug „off-label“ — meaning that it is not approved for that specific disorder — for their patients with mild cognitive impairment.

From data collected during the trial, the researchers looked at the association between BChE-K and changes in cognitive function. Using two tests that measure cognitive impairment, the Mini-Mental State Examination and the Clinical Dementia Rating Sum of Boxes, they found that people with the genetic variation who were treated with donepezil had greater changes in their scores than those who took placebos. They also found that those who took donepezil had a faster cognitive decline than those who took the placebo.

Physicians are increasingly using personalized medicine, including pharmacogenetics — the study of how genetics affect a person’s response to a drug — to tailor their patients‘ care. The findings reinforce the importance of physicians discussing the possible benefits and risks of this treatment with their patients, the researchers say.

Paper “Butyrylcholinesterase K and Apolipoprotein E-ɛ4 Reduce the Age of Onset of Alzheimer’s Disease, Accelerate Cognitive Decline, and Modulate Donepezil Response in Mild Cognitively Impaired Subjects”
Reprinted from materials provided by University of California – Los Angeles Health Sciences.

There is growing evidence showing a connection between Parkinson’s disease and the composition of the microbiome of the gut. A new study shows that Parkinson’s disease, and medications to treat Parkinson’s, have distinct effects on the composition of the trillions of bacteria that make up the gut microbiome.

The findings were published in Movement Disorders.

The study, which looked at 197 patients with Parkinson’s and 130 controls, indicated that Parkinson’s is accompanied by imbalance in the gut microbiome, with some species of bacteria present in larger numbers than in healthy individuals and other species diminished. Different medications used to treat Parkinson’s also appeared to affect the composition of the microbiome in different ways.

At this point, researchers do not know which comes first: Does having Parkinson’s cause changes in an individual’s gut microbiome, or are changes in the microbiome a predictor or early warning sign of Parkinson’s? What is known is that the first signs of Parkinson’s often arise as gastrointestinal symptoms such as inflammation or constipation.

One function of the microbiome is to help the body rid itself of xenobiotics — chemicals not naturally found in the body often arising from environmental pollutants. The study found evidence that the composition of bacteria responsible for removing those chemicals was different in individuals with Parkinson’s. This may be relevant because exposure to pesticides and herbicides in agricultural settings is known to increase the risk of developing Parkinson’s.

The researchers stress that the study of the microbiome is a relatively new field, and a better understanding of macrobiotics may provide unexpected answers for Parkinson’s disease and potentially other disorders.

Paper: “Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome”
Reprinted from materials provided by University of Alabama Birmingham.

In experiments with a protein called Ephexin5 that appears to be elevated in the brain cells of Alzheimer’s disease patients and mouse models of the disease, researchers say removing it prevents animals from developing Alzheimer’s characteristic memory losses. In a report on the studies, published in The Journal of Clinical Investigation, the researchers say the findings could eventually advance development of drugs that target Ephexin5 to prevent or treat symptoms of the disorder.

The work with Ephexin5 grew out of a paradox about one of Alzheimer’s disease’s defining features, the development of thick plaques in the brain composed of a protein called amyloid beta. Stemming the production of this protein is currently the major focus of efforts to develop new Alzheimer’s treatments, but it isn’t the amount of amyloid beta in patients‘ brains that correlates best with the severity of symptoms; rather, it’s the loss of so-called excitatory synapses, a type of cellular structure forged between two brain cells.

Although it’s not clear how amyloid beta and excitatory synapse loss are connected, researchers showed several years ago that Alzheimer’s patients have decreased brain levels of a protein called EphB2. Ephexin5 is a protein regulated by EphB2 and thought to be responsible for inhibiting the development of dendritic spines, small protrusions on the ends of nerve cells that are the location for most excitatory synapses.

In this study, the researchers used genetic engineering techniques that knocked out the gene that makes Ephexin5, thereby developing mouse Alzheimer’s disease models whose brain cells could not produce the protein. Although the animals still developed the characteristic Alzheimer’s amyloid plaques, they didn’t lose excitatory synapses, retaining the same number as healthy animals as they aged.

To see whether this retention of excitatory synapses in turn affected behavior related to memory tasks, the researchers trained healthy mice, mouse models of Alzheimer’s and Alzheimer’s models genetically engineered to lack Ephexin5 in two learning tasks: one that involved the ability to distinguish objects that had moved upon subsequent visits to the same chamber, and another that involved the ability to avoid chambers where they’d previously received a small electric shock.

While the typical Alzheimer’s disease model mice appeared unable to remember the moved objects or the shocks, the Alzheimer’s animals genetically engineered to be Ephexin5-free performed as well as healthy animals on the two tasks.

To better reflect the human scenario, in which the brain is exposed to amyloid beta for some time, probably decades, before any treatments might be administered, the researchers raised mouse models for Alzheimer’s disease into adulthood — allowing their brains to be exposed to excess amyloid beta for weeks — before injecting their brains with a short piece of genetic material that shut down Ephexin5 production. These mice performed just as well on the memory tasks as the healthy mice and those genetically engineered to produce no Ephexin5.

Together, these results suggest that too much Ephexin5 triggered by amyloid beta and reduced EphB2 signaling might be the reason why Alzheimer’s disease patients gradually lose their excitatory synapses, leading to memory loss — and that shutting down Ephexin5 production could slow or halt the disease.

Paper: “Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer’s-like impairment in mice”
Reprinted from materials provided by Johns Hopkins.

Researchers have identified early biomarkers of Huntington’s disease (HD) during examinations of HD sheep still at a pre-symptomatic stage of the disease. Up until this point, the five-year-old HD sheep displayed no signs of the illness, but this comprehensive study identified clear metabolic changes in the affected animals. These new findings reveal that Huntington’s disease affects important metabolic processes in the body prior to the appearance of physical symptoms.

During this study, blood samples were taken from normal and HD animals every two hours over a 24-hour period and their metabolic profiles assessed using a targeted metabolomics approach. Unlike previous research in this area, which was affected by external environmental factors that impacted upon metabolic profiling, sheep in this study were monitored in a well-controlled setting, negating any outside influences.

Blood measurements found startling differences in the biochemistry of the sheep carrying the HD gene, compared to the normal sheep. Significant changes were observed in 89 of the 130 metabolites measured in their blood, with increased levels of the amino acids, arginine and citrulline, and decreases in sphingolipids and fatty acids that are commonly found in brain and nervous tissue. The alterations in these metabolites, which include key components of the urea cycle and nitric oxide pathways (both vital body processes), suggest that both of these processes are dysregulated in the early stages of Huntington’s disease, and that the illness affects the body long before physical symptoms appear.

The identification of these biomarkers may help to track disease in pre-symptomatic patients, and could help researchers develop strategies to remedy the biochemical abnormalities.

Paper: “Metabolic profiling of presymptomatic Huntington’s disease sheep reveals novel biomarkers”
Reprinted from materials provided by University of Surrey.