Author Archives: jpnd

For the first time, a variant in UBQLN4 gene has been associated with amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig’s disease) – a progressive disease resulting in the loss of nerve cells that control muscle movement, which eventually leads to paralysis and death. The study, published in the journal eLife, also describes how this gene variant disrupts a cellular process that drives motor neuron development. This new insight opens the door to potential treatment targets for ALS.

The earlier discovery of mutations in UBQLN2 gene, which causes ALS and ALS/dementia, led to the screening of the UBQLN family of genes in a large cohort of patients with familial ALS, resulting in the identification of the UBQLN4 mutation.

Using a zebrafish model, researchers were able to reverse the defects caused by the UBQLN4 gene variant by inhibiting the beta catenin signaling pathway with the drug quercetin. These findings suggest that this pathway could be targeted for treatment. More research will be needed before a similar drug could be shown to work in people with ALS.

The researchers say that, at present, they don’t know how common the UBQLN4 gene variant is among people with ALS, so making this determination will be an important focus for future research.

Paper: “A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis”
Reprinted from materials provided by the Ann & Robert H. Lurie Children’s Hospital of Chicago.

Researchers have, for the first time, revealed the atomic structures of one of the two types of the abnormal filaments which lead to Alzheimer’s disease. Understanding the structures of these filaments will be key in developing drugs to prevent their formation.

The researchers, whose study is published today in Nature, believe the structures they have uncovered could also suggest how tau protein may form different filaments in other neurodegenerative diseases.

Alzheimer’s, the most common neurodegenerative disease, is characterised by the existence of two types of abnormal ‘amyloid’ forms of protein which form lesions in the brain. Tau forms filaments inside nerve cells and amyloid-beta forms filaments outside cells. Tau lesions appear to have a stronger correlation to the loss of cognitive ability in patients with the disease.

Almost thirty years ago, scientists identified tau protein as an integral component of the lesions found in Alzheimer’s and a range of other neurodegenerative diseases. But, until now, scientists have been unable to identify the atomic structure of the filaments.

The researchers extracted tau filaments from the brain of a patient who had died with Alzheimer’s disease. The filaments were then imaged using cryo-electron microscopy (cryo-EM). The researchers developed new software in order to calculate the structure of the filaments in sufficient detail to deduce the arrangement of the atoms inside them.

The researchers say that their study could lead to the development of new approaches to the diagnosis and treatment of Alzheimer’s disease.

Paper: “Cryo-EM structures of tau filaments from Alzheimer’s disease”
Reprinted from materials provided by the MRC.

Working with mouse, fly and human cells and tissue, researchers report new evidence that disruptions in the movement of cellular materials in and out of a cell’s control center — the nucleus — appear to be a direct cause of brain cell death in Huntington’s disease, an inherited adult neurodegenerative disorder. Moreover, they suggest, laboratory experiments with drugs designed to clear up these cellular “traffic jams” restored normal transport in and out of the nucleus and saved the cells.

In the study, published in Neuron, the researchers also conclude that potential treatments targeting the transport disruptions they identified in Huntington’s disease neurons may also work for other neurodegenerative diseases, such as ALS and forms of dementia.

In an earlier study, the team found out how a mutation in a gene — implicated in 40 percent of inherited ALS cases and 25 percent of inherited frontotemporal dementia cases — gums up transport in and out of the nucleus in neurons, ultimately shutting the cell down and leading to its death. The mutant gene makes RNA molecules that stick to a transport protein, RanGAP1. RanGAP1 in turn helps move molecules through nuclear pores that serve as passageways in the nucleus, letting proteins and genetic material flow in and out of it. They learned that this same mutation is also the most common cause of another disorder in which patients have Huntington’s-like symptoms without having the causative Huntington’s disease mutation. Additionally, they realized that other researchers previously showed that mutations in the nuclear pore protein NUP62 caused Huntington’s disease-like pathology. Because of such clues from others’ research, the scientists took on the task of investigating whether problems with nuclear transport and the nuclear pores also happened in neurons with Huntington’s disease.

The researchers used two mouse models of Huntington’s disease: one with a human version of the mutant Huntingtin protein and another with an aggressive form of the disease that contains only the first portion of the mouse Huntingtin protein. By using antibodies with glowing markers that bind to specific proteins and viewing the neurons under the microscope, they saw that the mutant Huntingtin protein clumped up in the same location of the cell as abnormal clumps of RanGAP1, the nuclear transport protein. It also clumped up in the same location as abnormal clumps of nuclear pore proteins NUP88 and NUP62.

They also observed this same clumping of Huntingtin protein with RanGAP1 and nuclear pore proteins to the wrong place in the cell in brain tissue and cultured brain cells derived from deceased patients with Huntington’s disease.

To further explore nuclear transport’s role in Huntington’s disease, the team took lab-grown mouse neurons and used chemical switches to a) turn on both an additional healthy copy of the RanGAP1 gene and a mutant version of Huntingtin; b) just turn on the mutant Huntingtin; or c) just turn on a healthy version of Huntingtin.

They then measured cell death and found that neurons with the healthy version of Huntingtin had about 17 percent of the neurons die off. Neurons with only the mutant version of Huntingtin were more likely to die, with about 33 percent dying off, but in neurons with both the mutant Huntingtin and the RanGAP1, only 24 percent of the neurons died off. The researchers think that some of the extra healthy RanGAP1 they introduced into diseased cells wasn’t bound up to the mutant Huntingtin and resumed normal nuclear transport.

Next, they looked at cell death in cultured neurons with a healthy or a mutant form of Huntingtin, or with a mutant form of Huntingtin that was treated with small amounts of an experimental drug called KPT-350, one that prevents a nuclear export protein, Exportin-1, from shuttling proteins and RNA out of the nucleus. Neurons with the healthy version of Huntingtin had about 18 percent die off, and neurons with the mutant version of Huntingtin had about 38 percent die off. Those treated with the nuclear export blocking drug had improved survival, with only about 22 percent of the cells die off. Blocking nuclear export seemed to prevent cells from dying and counteracted the defects in neurons with mutant Huntingtin.

According to the researchers, there is an average of 2000 nuclear pores per cell and each individual nuclear pore consists of multiple copies of more than 30 different proteins that each serve different functions. It may be that nuclear pores on neurons and other types of brain cells like glia are constructed of different combinations of these proteins, some of which may be more or less critical in various neurodegenerative diseases.

The team of researchers is currently working on answering this question using a new mouse model that will allow them to isolate these nuclear pore proteins from different cell types in the mouse brain to identify whether these nuclear pore components are in fact different based on brain cell types and brain locations.

Paper: “Mutant Huntingtin Disrupts the Nuclear Pore Complex”
Reprinted from materials provided by Johns Hopkins Medicine.

A team of researchers has found a way to measure tau levels in the blood. The method accurately reflects levels of tau in the brain that correlate with neurological damage. The study, in mice and a small group of people, could be the first step toward a noninvasive test for tau.

The study was published in Science Translational Medicine.

The researchers say that such a test potentially could be used to quickly screen for tau-based diseases, monitor disease progression and measure the effectiveness of treatments designed to target tau.

Tau is a normal brain protein involved in maintaining the structure of neurons. But when tau forms tangles, it damages and kills nearby neurons. A blood-based screening test, likely years away, would be a relatively easy way to identify people whose symptoms may be due to problems with tau, without subjecting them to potentially invasive, expensive or complicated tests.

In the brain, most tau proteins are inside cells, some are in tangles, and the remainder float in the fluid between cells. Such fluid constantly is being washed out of the brain into the blood, and tau comes with it. However, the protein is cleared from the blood almost as soon as it gets there, so the levels, while detectable, typically remain very low.

The team reasoned that if they could keep tau in the blood longer, the protein would accumulate to measurable levels. Allowing the protein to accumulate before measuring its levels would magnify – but not distort – differences between individuals, in the same way that enlarging a picture of a grain of sand alongside a grain of rice does not change the relative size of the two, but does make it easier to measure the difference between them.

The researchers injected a known amount of tau protein directly into the veins of mice and monitored how quickly the protein disappeared from the blood. The researchers showed that half the protein normally disappears in less than nine minutes. When they added an antibody that binds to tau, the half-life of tau was extended to 24 hours.

To determine whether the antibody could amplify tau levels in an animal’s blood high enough to be measured easily, they injected the antibody into mice. Within two days, tau levels in the mice’s blood went up into the easily detectable range. The antibody acted like a magnifying glass, amplifying tau levels so that differences between individuals could be seen more easily.

Tau levels in people’s blood also rose dramatically in the presence of the antibody. The researchers administered the antibody to four people with a tau disease known as progressive supranuclear palsy. Their blood levels of tau rose 50- to 100-fold within 48 hours.

Measuring tau levels in the blood is only useful if it reflects tau levels in the brain, where the protein does its damage, the researchers said.

Both high and low levels of tau in the fluid that surrounds the brain could be a danger sign. Alzheimer’s and chronic traumatic encephalopathy both are associated with high levels of soluble tau, whereas progressive supranuclear palsy and other genetic tau diseases are thought to be associated with low levels.

To see whether elevated brain tau is reflected in the blood, the researchers treated mice with a chemical that injures neurons. The chemical causes tau to be released from the dying neurons, thereby raising tau levels in the fluid surrounding the cells. The scientists saw a corresponding increase of tau in the blood in the presence of the anti-tau antibody.

Paper: “Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy”
Reprinted from materials provided by Washington University School of Medicine.

A team of researchers has identified silent, seizure-like activity in the hippocampus, a brain structure significantly affected in Alzheimer’s Disease, in two patients with Alzheimer’s disease and no known history of seizures. These alterations in the brain’s electrical activity could not be detected by standard EEG readings taken on the scalp and primarily occurred during sleep, a time when the preceding day’s memories are consolidated. The report was published in Nature Medicine.

The investigators describe two patients — both women in their 60s — who had developed symptoms suggestive of Alzheimer’s disease, such as confusion and repeatedly asking the same questions. Brain imaging studies and cerebrospinal fluid analysis for both patients were consistent with Alzheimer’s disease. It is common for patients with Alzheimer’s to experience fluctuations in their symptoms, but in both of these patients, those fluctuations were more exaggerated than typically seen.

While scalp EEG recordings did not reveal seizure-like activity, the investigators suspected that there may be undetected seizures within the hippocampus. They decided to try a more direct way of monitoring electrical activity in the hippocampus and related structures. Electrodes were placed adjacent to those structures on both sides of the brain through the foramen ovale (FO), naturally occurring openings at the base of the skull. Each patient’s brain activity was monitored simultaneously with both implanted electrodes and with scalp EEG for more than 24 to 72 hours.

In one patient, the FO electrodes revealed frequent bursts of electrical activity called spikes, often associated with seizures, most which were not detectible by scalp EEG. During a 12-hour period she experienced three seizures, all taking place during sleep but not producing any visible symptoms. Treatment with an anti-seizure medication eliminated the seizure-like activity, and in the following year, she experienced only one episode of confusion, which occurred after she missed several doses of her anti-seizure medication. FO electrode recording in the other patient also revealed frequent spiking during sleep, but anti-seizure treatment had to be discontinued because of adverse effects on her mood.

Since there is evidence that higher levels of neuronal activity can increase the production and deposition of Alzheimer’s associated proteins such as tau and amyloid-beta, understanding whether seizure-like activity accelerates the progression of Alzheimer’s disease will likely be a high priority for the researchers.

Paper: “Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer’s disease”
Reprinted from materials provided by Massachusetts General Hospital.