Tag Archives: Huntington’s

A protein complex called Polycomb Repressive Complex 2 (PRC2), which plays a critical role in forming specific classes of nerve cells in the brain during development, also plays an important role in the adult brain where it may contribute to Huntington’s disease and other neurodegenerative disorders, according to a study published in the journal Nature Neuroscience.

The study focuses on epigenetics, the study of changes in the action of human genes caused by molecules that regulate when, where, and to what degree our genetic material is activated. Protein complexes have an important role in the biochemical processes that are associated with the expression of genes. Some help to silence genes, whereas others are involved in the activation of genes. The importance of such complexes is emphasized by the fact that mice cannot live if they do not possess PRC2.

In the striatum, the brain region that regulates voluntary movements, the majority of neurons are called medium spiny neurons (MSNs), so-called because of their spiny appearance. MSNs are further characterized by the expression of a specific set of genes that determines their unique identity and function. Once specified, an MSN’s identity needs to be maintained throughout life in order to ensure normal motor function.

PRC2 is an epigenetic gene regulator that represses or silences a given gene’s expression. While previous research has found PRC2 to be critical for normal brain development, the role of this protein complex in maintaining the specialization and function of adult MSNs had remained a mystery.

To study the role of PRC2 in MSN formation and function, the researchers generated a mouse model that lacks the PRC2 complex specifically in neurons in the forebrain. The research team found that neurons in mice that lack PRC2, including mice that lacked PRC2 in MSNs, showed inappropriate reactivation of genes that are usually turned off in these cells, and inhibited the expression of genes that are usually turned on and which are essential to the MSN’s specific function. The data suggests that PRC2 not only governs the process of brain cell development but also that PRC2 helps to maintain MSNs’ identity into the animal’s adult life and plays an active role in determining whether the neuron should live or die.

Closer examination of the altered genes in the striatum of the mice that lacked PRC2 revealed that many of these genes controlled by PRC2 are those known to control the process whereby brain cells self-destruct. Consistent with this finding, the PRC2-lacking mice showed signs of progressive cell death in the striatum and had smaller brain mass then non-mutant mice. In addition, these mice developed a progressive and fatal neurodegenerative disorder reminiscent of Huntington’s disease in humans, suggesting that disruption of PRC2 may contribute to neurodegenerative disorders.

Paper: “Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration”
Reprinted from materials provided by Mount Sinai Hospital.

Ten international JPND working groups recommended for funding

The EU Joint Programme Neurodegenerative Disease Research (JPND) has released the results of a “rapid-action” call to support working groups of leading scientists to bring forward novel approaches that will enhance the use of brain imaging for neurodegenerative disease research.

Ten working groups have been recommended for funding to address the methodological challenges facing different imaging modalities, among them MRI, PET, ultrasound, MEG and EEG, as well as multimodal approaches. The working groups cover a range of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Frontotemporal dementia and Huntington’s disease.

“Brain imaging has made enormous progress in recent years and is currently one of the most promising avenues in neurodegenerative disease research,” said Professor Thomas Gasser, Chair of the JPND Scientific Advisory Board. “If we can solve the challenges in the field, brain imaging could rapidly lead to faster and better diagnoses as well as a deeper understanding of the fundamental aspects and mechanisms of neurodegeneration.”

Although imaging techniques have brought about a dramatic improvement in the understanding of neurodegenerative diseases, there remain a number of significant challenges in the field. These include the execution of multi-centre clinical trials of an unprecedented scale, data transfer across imaging centres and the use of imaging for diagnostics and for measuring clinical outcomes.

To address these questions, on January 8, 2016, JPND launched a call for community-led working groups on harmonisation and alignment in brain imaging methods. The proposals recommended for funding are for top scientists to come together and propose, through ‘best practice’ guidelines and/or methodological frameworks, how to overcome key barriers to the use of imaging in neurodegenerative disease research.

The call attracted proposals with partners from across Europe and beyond, including Asia, Australia, North America and South America. A notable number of groups based in the United States were involved in responses to the call. Funding decisions were based upon scientific evaluation and recommendations to sponsor countries by a JPND peer review panel.

“This call perfectly embodies JPND’s mission and objectives,” said Professor Philippe Amouyel, Chair of the JPND Management Board. “The purpose of JPND is to strengthen coordination and collaboration in neurodegenerative disease research across different countries. We want to ensure that research efforts are not duplicated, to build consensus and to accelerate a path toward a cure that works. This call convenes groups of leading experts to hammer out the hard questions, including the challenges of interoperability and shared and open data, to allow researchers to more rapidly and more fully exploit imaging techniques going forward.”

Each working group is expected to run for a maximum of 9 months. The outputs of the working groups are to be produced by the end of the funding period, and will be published on the JPND website and used for further JPND actions. In addition, a common workshop will be organised to bring together and present the recommendations of each working group, encouraging the further exchange of ideas and wider dissemination to different stakeholder groups.

For more information on the working groups recommended for funding, click here.

A study appearing in the journal Neuron suggests there may be a new way to change the damaging course of Huntington’s disease.

Neurobiologists have shown that reducing the aberrant accumulation of a particular form of the mutant Huntingtin protein corresponds to improvement in symptoms and neuroinflammation in HD mice.

They showed this by targeting and modulating levels of PIAS1 — a protein implicated in cancer and other diseases — which they found led to the reduction of the mutant Huntington protein. The work suggests that changing levels of the PIAS1 protein and targeting this pathway could have a benefit to disease.

Source: Reprinted from materials provided by the University of California, Irvine.

Paper: “PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington’s Disease-Associated Phenotypes In Vivo”

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 shown how brain connections, or synapses, are lost early in Alzheimer’s disease and demonstrated that the process starts — and could potentially be halted — before telltale plaques accumulate in the brain. Their work, published online by Science, suggests new therapeutic targets to preserve cognitive function early in Alzheimer’s disease.

The researchers show in multiple Alzheimer’s mouse models that mechanisms similar to those used to “prune” excess synapses in the healthy developing brain are wrongly activated later in life. By blocking these mechanisms, they were able to reduce synapse loss in the mice.

Currently, there are five FDA-approved drugs for Alzheimer’s, but these only boost cognition temporarily and do not address the root causes of cognitive impairment in Alzheimer’s. Many newer drugs in the pipeline seek to eliminate amyloid plaque deposits or reduce inflammation in the brain, but the new research from Boston Children’s suggests that Alzheimer’s could be targeted much earlier, before these pathologic changes occur.

“Synapse loss is a strong correlate of cognitive decline,” says Beth Stevens, assistant professor in the Department of Neurology at Boston Children’s, senior investigator on the study and a recent recipient of the MacArthur “genius” grant. “We’re trying to go back to the very beginning and see how synapse loss starts.”

The researchers looked at Alzheimer’s — a disease of aging — through an unusual lens: normal brain development in infancy and childhood. Through years of research, the Stevens lab has shown that normal developing brains have a process to “prune” synapses that aren’t needed as they build their circuitry.

“Understanding a normal developmental process deeply has provided us with novel insight into how to protect synapses in Alzheimer’s and potentially a host of other diseases,” says Stevens, noting that synapse loss also occurs in frontotemporal dementia, Huntington’s disease, schizophrenia, glaucoma and other conditions.

In the Alzheimer’s mouse models, the team showed that synapse loss requires the activation of a protein called C1q, which “tags” synapses for elimination. Immune cells in the brain called microglia then “eat” the synapses — similar to what occurs during normal brain development. In the mice, C1q became more abundant around vulnerable synapses before amyloid plaque deposits could be observed.

When Stevens and colleagues blocked C1q, a downstream protein called C3, or the C3 receptor on microglia, synapse loss did not occur.

“Microglia and complement are already known to be involved in Alzheimer’s disease, but they have been largely regarded as a secondary event related to plaque-related neuroinflammation, a prominent feature in progressed stages of Alzheimer’s,” notes Soyon Hong, the Science paper’s first author. “Our study challenges this view and provides evidence that complement and microglia are involved much earlier in the disease process, when synapses are already vulnerable, and could potentially be targeted to preserve synaptic health.”

A human form of the antibody Stevens and Hong used to block C1q, known as ANX-005, is in early therapeutic development with Annexon Biosciences (San Francisco) and is being advanced into the clinic. The researchers believe it has potential to be used someday to protect against synapse loss in a variety of neurodegenerative diseases.

“One of the things this study highlights is the need to look for biomarkers for synapse loss and dysfunction,” says Hong. “As in cancer, if you treat people at a later stage of Alzheimer’s, it may already be too late.”

The researchers also found that the beta-amyloid protein, C1q and microglia work together to cause synapse loss in the early stages of Alzheimer’s. The oligomeric form of beta-amyloid (multiple units of beta-amyloid strung together) is already known to be toxic to synapses even before it forms plaque deposits, but the study showed that C1q is necessary for this effect. The converse was also true: microglia engulfed synapses only when oligomeric beta-amyloid was present.

Source: Reprinted from materials provided by Boston Children’s Hospital
Paper: “Complement and microglia mediate early synapse loss in Alzheimer mouse models”

Protein aggregates are deemed to be one reason for the death of nerve cells in disorders such as Alzheimer’s or Huntington’s disease. As researchers report in the current issue of Nature, they have now decoded a new cellular mechanism for the development of aggregates. Missing stop signals in the production of proteins lead erroneously to long lysine chains at the end of the protein. This in turn blocks the ribosomes, the cell’s protein factory. Healthy cells detect blocked ribosomes and rapidly destroy useless proteins. If the necessary quality control machinery does not function properly, defective proteins accumulate and form toxic aggregates.

In order to be able to treat neurodegenerative disorders in future, researchers have for many years been studying the cellular causes for the death of nerve cells. A determining cause is believed to be protein deposits – aggregates of misfolded proteins.

In each cell, proteins perform vital functions, acting as small molecular machines. The mRNA contains a start signal, the information about the protein structure, a stop signal and, at the end, a poly(A) tail. If the blueprint is damaged, for example due to radiation or mutagenic substances, this can lead to the loss of this stop signal. As a result, once the protein has been manufactured in the ribosomes, the completed protein cannot be released. Instead, the poly(A) tail is interpreted as the blueprint and additional amino acids are attached. The lysine chain that is positively charged as a result blocks the protein factory and the manufacture of protein comes to a standstill.

Healthy cells have a very efficient quality control process when it comes to the manufacture of protein. Misfolded and useless proteins are selected, repaired or rapidly destroyed.

Using a mouse model, the researchers can now demonstrate the fatal consequences of a quality control malfunction. Animals with the relevant mutation show symptoms of advanced neurodegeneration and a restricted ability to move.

The protein aggregates that develop have a sticky surface and act as a seed. They ultimately also bind functioning proteins, which are free of defects and vital for the cell. As a result, the cell is destabilized and, in the long run, is damaged.

Source: Max Planck Institute of Biochemistry

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

Researchers have discovered that an existing compound, previously tested for diabetes, offers hope for slowing Huntington’s Disease (HD) and its symptoms.

The study was published in Nature Medicine.

“We’re very excited by our pre-clinical testing of this compound (KD3010),” said Albert La Spada, MD, PhD, professor of pediatrics, cellular and molecular medicine and neurosciences at UC San Diego School of Medicine. “It improved motor function, reduced neurodegeneration and increased survival in a mouse model of Huntington’s disease and reduced toxicity in neurons generated from human HD stem cells.”

The discovery of the drug’s potential in HD builds upon more than a decade of research into the disorder’s underlying molecular pathology. Much of that work has centered on misfolded proteins, which are known to be key culprits in HD and several other neurodegenerative diseases.

At the cellular level, the drug improved mitochondrial energy production and helped mice get rid of the misfolded proteins. Since misfolded proteins also underlie Alzheimer’s, Parkinson’s and other neurodegenerative disorders, researchers hope that, if successful in HD, the compound can also be tested in other related neurological diseases.

Source: UC San Diego

Caltech biologists have modified a harmless virus in such a way that it can successfully enter the adult mouse brain through the bloodstream and deliver genes to cells of the nervous system. The virus could help researchers map the intricacies of the brain and holds promise for the delivery of novel therapeutics to address diseases such as Alzheimer’s and Huntington’s. In addition, the screening approach the researchers developed to identify the virus could be used to make additional vectors capable of targeting cells in other organs.

To sneak genes past the blood-brain barrier, the researchers used a new variant of a small, harmless virus called an adeno-associated virus (AAV). The researchers developed a high-throughput selection assay, CREATE (Cre REcombinase-based AAV Targeted Evolution), that allowed them to test millions of viruses in vivo simultaneously and to identify those that were best at entering the brain and delivering genes to a specific class of brain cells known as astrocytes.

They started with the AAV9 virus and modified a gene fragment that codes for a small loop on the surface of the capsid—the protein shell of the virus that envelops all of the virus’ genetic material. Using a common amplification technique, known as polymerase chain reaction (PCR), they created millions of viral variants.

Then they used their novel selection process to determine which variants most effectively delivered genes to astrocytes in the brain. Importantly, the new process relies on strategically positioning the gene encoding the capsid variants on the DNA strand between two short sequences of DNA, known as lox sites. These sites are recognized by an enzyme called Cre recombinase, which binds to them and inverts the genetic sequence between them. By injecting the modified viruses into transgenic mice that only express Cre recombinase in astrocytes, the researchers knew that any sequences flagged by the lox site inversion had successfully transferred their genetic cargo to the target cell type—here, astrocytes.

After one week, the researchers isolated DNA from brain and spinal cord tissue, and amplified the flagged sequences, thereby recovering only the variants that had entered astrocytes.

Next, they took those sequences and inserted them back into the modified viral genome to create a new library that could be injected into the same type of transgenic mice. After only two such rounds of injection and amplification, a handful of variants emerged as those that were best at crossing the blood-brain barrier and entering astrocytes.

Through this selection process, the researchers identified a variant dubbed AAV-PHP.B as a top performer. To test AAV-PHP.B, the researchers used it to deliver a gene that codes for a protein that glows green, making it easy to visualize which cells were expressing it. They injected the AAV-PHP.B or AAV9 (as a control) into different adult mice and after three weeks used the amount of green fluorescence to assess the efficacy with which the viruses entered the brain, the spinal cord, and the retina.

“We could see that AAV-PHP.B was expressed throughout the adult central nervous system with high efficiency in most cell types,” says Gradinaru. Indeed, compared to AAV9, AAV-PHP.B delivers genes to the brain and spinal cord at least 40 times more efficiently.

The research was published in the journal Nature Biotechnology.

Source: Caltech

Researchers have shown that the core of the protein clumps found in the brains of people with Huntington’s disease have a distinctive structure, a finding that could shed light on the molecular mechanisms underlying the neurodegenerative disorder. The findings were published in the Proceedings of the National Academy of Sciences.

In Huntington’s and several other progressive brain diseases, certain proteins aggregate to form plaques or deposits in the brain, said senior investigator Patrick C.A. van der Wel, Ph.D., assistant professor of structural biology at Pitt School of Medicine.

“Despite decades of research, the nature of the protein deposition has been unclear, which makes it difficult to design drugs that affect the process,” he said. “Using advanced nuclear magnetic resonance spectroscopy, we were able to provide an unprecedented view of the internal structure of the protein clumps that form in the disease, which we hope will one day lead to new therapies.”

The gene associated with Huntington’s makes a protein that has a repetitive sequence called polyglutamine. In the 1990s, it was discovered that the patients have mutated proteins in which this sequence is too long, yet it has remained unclear how exactly this unusual mutation causes the protein to misbehave, clump together and cause the disease.

“This is exciting because it may suggest new ways to intervene with these disease-causing events,” Dr. van der Wel said. “For the first time, we were able to really look at the protein structure in the core of the deposits formed by the mutant protein that causes Huntington’s. This is an important breakthrough that provides crucial new insights into the process of how the protein undergoes misfolding and aggregation.

He added Huntington’s is one of many neurodegenerative diseases in which unusual protein deposition occurs in the brain, suggesting similar biochemical mechanisms may be involved. Lessons learned in this disease could help foster understanding of how these types of diseases develop, and what role the protein aggregates play.

Source:  University of Pittsburgh