Category Archives: Research News (General)

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.

Scientists have identified a mechanism in the molecular machinery of the cell that could help explain how neurons begin to falter in the initial stages of Alzheimer’s disease, even before amyloid clumps appear. This hypothesis centers on human genes critical for the healthy functioning of mitochondria, the energy factories of the cell, which are riddled with mobile chunks of DNA called Alu elements.

The researchers describe their work in a paper published online in Alzheimer’s & Dementia.

If these “jumping genes” lose their normal controls as a person ages, they could start to wreak havoc on the machinery that supplies energy to brain cells — leading to a loss of neurons and ultimately dementia. And if this “Alu neurodegeneration hypothesis” holds up, it could help identify people at risk sooner, before they develop symptoms, or point to new ways to delay onset or slow progression of the disease.

The dominant idea guiding Alzheimer’s research for 25 years has been that the disease results from the abnormal buildup of hard, waxy amyloid plaques in the parts of the brain that control memory. But drug trials using anti-amyloid drugs have failed, leading some researchers to theorize that amyloid buildup is a byproduct of the disease, not a cause.

This study builds on an alternative hypothesis. First proposed in 2004, the “mitochondrial cascade hypothesis” posits that changes in the cellular powerhouses, not amyloid buildup, are what cause neurons to die.

Most mitochondrial proteins are encoded by genes in the cell nucleus before reaching their final destination in mitochondria. In 2009, neurologists identified a non-coding region in a gene called TOMM40 that varies in length. The team of researchers found that the length of this region can help predict a person’s Alzheimer’s risk and age of onset. They wondered if the length variation in TOMM40 was only part of the equation. The researchers analysed the corresponding gene region in gray mouse lemurs, teacup-sized primates known to develop amyloid brain plaques and other Alzheimer’s-like symptoms with age. They found that in mouse lemurs alone, but not other lemur species, the region is loaded with short stretches of DNA called Alus.

Found only in primates, Alus belong to a family of retrotransposons or “jumping genes,” which copy and paste themselves in new spots in the genome. If the Alu copies present within the TOMM40 gene somehow interfere with the path from gene to protein, the scientists could help explain why mitochondria in nerve cells stop working.

The TOMM40 gene encodes a barrel-shaped protein in the outer membrane of mitochondria that forms a channel for molecules — including the precursor to amyloid — to enter. The scientists used 3D modeling to show that Alu insertions within the TOMM40 gene could make the channel protein it encodes fold into the wrong shape, causing the mitochondria’s import machinery to clog and stop working. The researchers say that such processes likely get underway before amyloid builds up, so they could point to new or repurposed drugs for earlier intervention.

The TOMM40 gene is one example, but if Alus disrupt other mitochondrial genes, the same basic mechanism could help explain the initial stages of other neurodegenerative diseases too, including Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS).

Paper: “The Alu neurodegeneration hypothesis: A primate-specific mechanism for neuronal transcription noise, mitochondrial dysfunction, and manifestation of neurodegenerative disease”
Reprinted from materials provided by Duke.

Researchers have shown for the first time that Amyotrophic Lateral Sclerosis (ALS) and schizophrenia have a shared genetic origin, indicating that the causes of these diverse conditions are biologically linked. The work was published in Nature Communications.

By analyzing the genetic profiles of almost 13,000 ALS cases and over 30,000 schizophrenia cases, the research confirms that many of the genes that are associated with these two very different conditions are the same.

In fact, the research has shown an overlap of 14% in genetic susceptibility to the adult onset neuro-degeneration condition ALS and the developmental neuropsychiatric disorder schizophrenia.
While overlaps between schizophrenia and other neuropsychiatric conditions including bipolar affective disorder and autism have been shown in the past, this is the first time that an overlap in genetic susceptibility between ALS and psychiatric conditions has been shown.

The research was prompted by earlier epidemiological studies that showed that people with ALS were more likely than expected to have other family members with schizophrenia, and to have had another family member who had committed suicide.

The researchers say that they will continue to study the links between ALS and psychiatric conditions using modern genetics, epidemiology and neuroimaging, and in this way will develop new and more effective treatments that are based on stabilizing disrupted brain networks.

Paper: “Genetic correlation between amyotrophic lateral sclerosis and schizophrenia”
Reprinted from materials provided by Trinity College Dublin.

Researchers have found that engaging in mentally stimulating activities, even late in life, may protect against new-onset mild cognitive impairment, which is the intermediate stage between normal cognitive aging and dementia. The study found that cognitively normal people 70 or older who engaged in computer use, craft activities, social activities and playing games had a decreased risk of developing mild cognitive impairment. The results were published in JAMA Neurology.

The researchers followed 1,929 cognitively normal participants for an average duration of four years. After adjusting for sex, age and educational level, researchers discovered that the risk of new-onset mild cognitive impairment decreased by 30 percent with computer use, 28 percent with craft activities, 23 percent with social activities, and 22 percent with playing games.

Researchers conducted a neurocognitive assessment at the time of enrollment in the study, with evaluations every 15 months. Following the assessment, an expert consensus panel made the classification of normal cognition or mild cognitive impairment for each study participant, based on published criteria.

The benefits of being cognitively engaged even were seen among apolipoprotein E (APOE) ε4 carriers. APOE ε4 is a genetic risk factor for mild cognitive impairment and Alzheimer’s dementia. However, for APOE ε4 carriers, only computer use and social activities were associated with a decreased risk of mild cognitive impairment.

Paper: “Association Between Mentally Stimulating Activities in Late Life and the Outcome of Incident Mild Cognitive Impairment, With an Analysis of the APOE ε4 Genotype”
Reprinted from materials provided by Mayo Clinic.

The most common genetic cause of the brain diseases frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a mutation in the C9orf72 gene. Researchers have demonstrated that if an affected parent passes on this mutation, the children will be affected at a younger age (than the parent). There are no indications that the disease progresses more quickly. These results were published JAMA Neurology.

After Alzheimer’s disease, FTD is the most common form of dementia in young patients. A fraction of FTD patients show symptoms consistent with ALS, a disease in which the nerve cells that control the muscles in the brain and spinal cord are affected. This causes ALS patients to progressively lose muscle mass, resulting in loss of strength in the limbs and problems with speaking, swallowing, and breathing. ALS is more common without FTD symptoms.

The mutation in C9orf72 consists of a repetition of a short DNA sequence GGGGCC which can expand in patients up to several thousands of repetitions. It is not yet known why some patients get FTD and others ALS.

The age at first presentation of disease symptoms ranges in patients from 29 to 82 years, even in patients from the same family. Until recently, there was no explanation for this high variability. The researchers demonstrated in 2016 that the age of onset is determined by the number of GGGGCC repeats: the more repetitions, the earlier the age of onset. In C9orf72 families in which the affected parent had a late age of onset and their affected children an earlier age of onset, the researchers provided evidence that the GGGGCC repeat in the C9orf72 gene expanded from a short sequence of repeats (less than 200 repeats) to a long one (more than a thousand).

In the new study, the researchers looked at the age of onset across multiple generations. They found that in successive generations of C9orf72 families, the age of onset was markedly different. According to the researchers, most of the patients from the later generations — i.e., the children or grandchildren of the oldest subjects – showed disease symptoms at a younger age, even as the disease was shown to progress no more quickly than in older generations.

Paper: “Children of patients with C9orf72 mutations are at a greater risk of frontotemporal dementia or ALS at a younger age”
Reprinted from materials provided by VIB – Flander Interuniversity Institute for Institute for biotechnology.

In a paper published in the journal Cell Death and Differentiation, a research team has reported that a gene called ATF4 plays a key role in Parkinson’s disease, acting as a ‘switch’ for genes that control mitochondrial metabolism for neuron health. By discovering the gene networks that orchestrate the process of ATF4 expression, the researchers have singled out new therapeutic targets that could prevent neuron loss.

Some forms of Parkinson’s are caused by mutations in the genes PINK1 and PARKIN, which are instrumental in mitochondrial quality control. Fruit flies with mutations in these genes accumulate defective mitochondria and exhibit Parkinson’s-like changes, including loss of neurons.

The researchers used PINK1 and PARKIN mutant flies to search for other critical Parkinson’s genes — and using a bioinformatics approach discovered that the ATF4 gene plays a key role.

The findings build upon recent research that discovered several genes that protect neurons in Parkinson’s disease, creating possibilities for new treatment options.

Two of the genes — PINK1 and PARKIN — affect how mitochondria break down amino acids to generate nucleotides – the metabolism of these molecules generates the energy that cells need to live.

Dysfunctional mitochondrial metabolism has been linked to Parkinson’s and research has previously showed that boosting this metabolism with nucleotides can protect neurons.

Paper: “dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective”
Reprinted from materials provided by University of Leicester.

Disabling a part of brain cells that acts as a tap to regulate the flow of proteins has been shown to cause neurodegeneration, a new study has found.

The research, which was carried out in mice, focused on the Golgi apparatus — a compartment inside all cells in the body that controls the processing and transport of proteins. It is fundamental for the growth of the cell membrane and also for the release of many types of proteins such as hormones, neurotransmitters and the proteins that make up our skeletons.

The study was published in the Proceedings of the National Academy of Sciences.

Although the function of the Golgi apparatus, named after its Italian discoverer, is well understood, it has not been previously been shown to have a role in neurodegeneration. With these results the scientists think they may have found a new avenue to explore in the search for the causes of some neurodegenerative diseases.

How much the Golgi apparatus contributes to the major neurodegenerative diseases such as Alzheimer’s or Parkinson’s is something that is currently unclear, though other studies have made this link.

Paper: “Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice”
Reprinted from materials provided by University of Manchester.

Progressive supranuclear palsy (PSP) is a brain disease that belongs to a group of neurological diseases referred to as tauopathies. PSP impairs eye movements, locomotion, balance control, and speech, and is currently incurable. Now scientists have discovered a molecular mechanism that may help in the search for effective treatments for PSP and potentially other tauopathies. Their study, which focuses on a protein called PERK (protein kinase RNA-like endoplasmic reticulum kinase), was published in EMBO Molecular Medicine.

In tauopathies, a molecule called tau forms clumps rather than stabilizing the cytoskeleton as it normally does. Affected neurons can degenerate or even perish. To prevent such events, pathological molecules are normally repaired or disposed of by the organism. The protein PERK is part of such a maintenance system. However, in PSP, this mechanism appears to be defective. In previous studies, the researchers had found that the risk for PSP is associated with variants of the PERK gene, and that loss of PERK function induces tau pathology in humans. For the current study, they examined the functioning of this protein more closely, to see how its effects could be positively influenced. To this end, they investigated samples of brain tissue from deceased patients, cell cultures and mice with a genetic disposition for PSP.

They found that the disease sequelae decrease when PERK is activated with pharmaceuticals. Their findings, the researchers say, show that PERK is an important part of the disease mechanism.

The scientists see potential for tackling other brain diseases because PERK helps eliminate the abnormal tau molecules that also occur in other diseases such as Alzheimer’s disease.

Paper: “A protein called PERK may be a target for treating progressive supranuclear palsy: Acting upon the maintenance system of neurons alleviates disease sequelae in laboratory experiments”
Reprinted from materials provided by DZNE- German Center for Neurodegenerative Disease.