Tag Archives: Huntington’s

The EU Joint Programme – Neurodegenerative Disease Research (JPND) has announced a rapid-action call inviting leading scientists in the field to bring forward novel approaches that will enhance the use of brain imaging for neurodegenerative disease research.

Imaging techniques such as MR, PET and EEG mapping have brought about a dramatic improvement in the understanding of neurodegenerative diseases such as Alzheimer’s disease. In recent years, access to cutting-edge imaging technologies and platforms has expanded, and advances have been made in the harmonisation of acquisition procedures across scanners and vendors. However, fully capitalising on the use of brain imaging technologies for neurodegeneration research will require the development of new methodologies and the ability to achieve image acquisition and analysis at scale and at the global level.

The aim of the call is to establish a limited number of transnational working groups to address the key challenges facing the use of new and innovative brain imaging techniques in neurodegenerative disease research. The working groups will be community-led and will establish ‘best practice’ guidelines and/or methodological frameworks to overcome these barriers. Each working group can bid up to €50,000 for the support of its activities, which are expected to run for a maximum of 9 months.

According to Professor Philippe Amouyel, Chair of the JPND Management Board:

“JPND recognises that state-of-the-art brain imaging techniques are a vital resource for neurodegenerative disease research. However, achieving scalability for these technologies poses new challenges. For this reason, we’ve launched a rapid-action call inviting international research teams to address the most urgent issues in harmonisation and alignment in neuroimaging. The establishment of effective new guidelines and methodological frameworks will represent a critical step toward the full exploitation of brain imaging in neurodegenerative disease research.”

The following neurodegenerative diseases are included in the call:

  • Alzheimer’s disease and other dementias
  • Parkinson’s disease and PD‐related disorders
  • Prion diseases
  • Motor neuron diseases
  • Huntington’s disease
  • Spinocerebellar ataxia (SCA)
  • Spinal muscular atrophy (SMA)

Proposals must be submitted by 23:59H C.E.T. on March 10, 2016.

For more information about the call, please click here.

 

A new study finds that a component of aspirin binds to an enzyme called GAPDH, which is believed to play a major role in neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases.

Researchers discovered that salicylic acid, the primary breakdown product of aspirin, binds to GAPDH, thereby stopping it from moving into a cell’s nucleus, where it can trigger the cell’s death. The study, which appears in the journal PLOS ONE, also suggests that derivatives of salicylic acid may hold promise for treating multiple neurodegenerative diseases.

The researchers performed high-throughput screens to identify proteins in the human body that bind to salicylic acid. GAPDH, (Glyceraldehyde 3-Phosphate Dehydrogenase), is a central enzyme in glucose metabolism, but plays additional roles in the cell. Under oxidative stress—an excess of free radicals and other reactive compounds—GAPDH is modified and then enters the nucleus of neurons, where it enhances protein turnover, leading to cell death.

The anti-Parkinson’s drug deprenyl blocks GAPDH’s entry into the nucleus and the resulting cell death. The researchers discovered that salicylic acid also is effective at stopping GAPDH from moving into the nucleus and preventing cell death.

“The enzyme GAPDH, long thought to function solely in glucose metabolism, is now known to participate in intracellular signaling,” said co-author Solomon Snyder, professor of neuroscience at Johns Hopkins University in Baltimore. “The new study establishes that GAPDH is a target for salicylate drugs related to aspirin, and hence may be relevant to the therapeutic actions of such drugs.”

Source: Boyce Thompson Institute

Researchers have made a new discovery about Huntington’s disease, showing that the gene that causes the fatal disorder makes an unexpected “cocktail” of mutant proteins that accumulate in the brain.

The findings are significant because these newly identified mutant proteins kill neurons and build up in regions of the brain that are most affected by the disease. The findings were published in the journal Neuron.

The researchers examined the brains of 12 deceased adult and juvenile patients with Huntington’s disease. They found novel proteins that were abundant in areas of patients’ brains that showed cell death, neuronal loss and other signs of disease, including neuroinflammation.

Along with a protein already implicated in Huntington’s disease, the researchers found four proteins that also contribute to the disease pathology. The disease stems from a genetic mutation in the Huntingtin gene that produces too many copies of a DNA segment known as CAG, which gives rise to a longer Huntingtin protein with toxic effects. However, researchers found that this DNA repeat mutation can undergo a process known as repeat associated non-ATG (RAN) translation, producing four additional damaging repeat proteins that accumulate in the brain. This was a surprise to the researchers because these RAN proteins are made without a signal in the genetic code that was previously thought to be required for protein production. Each of the four RAN proteins contains long repeats of certain single protein building blocks, or amino acids.

Finding these novel RAN proteins in degenerated areas of the brain that were negative for the previously known mutant Huntingtin protein was crucial to linking them to the disease, said Monica Bañez-Coronel, Ph.D., a postdoctoral associate and the first author of the journal article.

Source: University of Florida

The EU Joint Programme – Neurodegenerative Disease Research (JPND) will shortly begin another action to support working groups on “Harmonisation and Alignment in Brain Imaging Methods for Neurodegeneration”.

The aim of the call is to establish a limited number of transnational, JPND-sponsored expert working groups to address issues of key relevance for the future use of brain imaging techniques in ND research. Each working group can bid up to €50,000 for support of its activities, which are expected to run for a maximum of 6 months.

This will be a 1-step call, anticipated to launch in early January 2016, with a likely submission deadline of March 2016. Further details will be provided on the call launch date in January 2016. However, any new ideas to tackle harmonisation and alignment in brain imaging will be welcome. For example, this may include:

  • Harmonisation of acquisition for current markers (acquisition and harmonisation of procedures, for example, for MR, FDG PET, and EEG signals)
  • Simplification of web access to image analysis environments (improving the secure access to innovative web-based image analysis environments for neurodegenerative diseases)
  • Innovative PET molecular markers (fostering the use of established and experimental PET methods)
  • Innovative ultra-high field (UHF) MR markers

Please Note:

  • Proposals are not limited to these topics, and may cover other topics within harmonisation and alignment of brain imaging methods.
  • All information regarding future JPND Call topics is subject to change.
  • Final call information will be published on the JPND website (www.jpnd.eu).

The diseases covered by JPND are:
– Alzheimer’s disease (AD) and other dementias
– Parkinson’s disease (PD) and PD‐related disorders
– Prion disease
– Motor neurone diseases (MND)
– Huntington’s Disease (HD)
– Spinocerebellar ataxia (SCA)
– Spinal muscular atrophy (SMA)

 

‘Seeding’ property provides new focus for treatment to delay progression of disorder

By identifying in spinal fluid how the characteristic mutant proteins of Huntington’s disease spread from cell to cell, researchers have created a new method to quickly and accurately track the presence and proliferation of these neuron-damaging compounds — a discovery that may accelerate the development of new drugs to treat this incurable disease.

The researchers added that the cell-to-cell “seeding” property of these mutant proteins seems to be a critical part of the disease’s progression. Their findings also advance a new drug-discovery approach: stopping the cellular transfer of the seeding compounds. Study results appear online in the journal “Molecular Psychiatry”.

With several therapeutic approaches in development for Huntington’s disease, there is a need for easily accessible biomarkers to monitor disease progression and therapy response.

Researchers at Leiden University Medical Center in The Netherlands have discovered a panel of five genes whose expression in whole blood correlates with progression of Huntington’s disease.

In a study published in The European Journal of Human Genetics, the group reported that transcriptome analysis of 91 Huntington’s mutation carriers, about one third of whom were presymptomatic, and 33 controls yielded 167 differentially expressed genes. Twelve of the top 20 genes were validated using a different technique, and five of these proved significant in a smaller, independent cohort as well.

The authors suggest a first empiric formula predicting total motor score from the expression levels of our biomarker panel. Their data supports the view that peripheral blood is a useful source to identify biomarkers for Huntington’s disease and monitor disease progression in future clinical trials.

Age-related neurodegenerative disorders including Alzheimer’s disease and Huntington’s disease (HD) consistently show elevated DNA damage, but the relevant molecular pathways in disease pathogenesis remain unclear. One attractive gene is that encoding the ataxia-telangiectasia mutated (ATM) protein, a kinase involved in the DNA damage response, apoptosis, and cellular homeostasis. Loss-of-function mutations in both alleles of ATM cause ataxia-telangiectasia in children, but heterozygous mutation carriers are disease-free. Persistently elevated ATM signaling has been demonstrated in Alzheimer’s disease and in mouse models of other neurodegenerative diseases.

This new study shows that ATM signaling was consistently elevated in cells derived from HD mice and in brain tissue from HD mice and patients. ATM knockdown protected from toxicities induced by mutant Huntingtin (mHTT) fragments in mammalian cells and in transgenic Drosophila models.

By crossing the murine Atm heterozygous null allele onto BACHD mice expressing full-length human mHTT, the researchers show that genetic reduction of Atm gene dosage by one copy ameliorated multiple behavioral deficits and partially improved neuropathology. Small-molecule ATM inhibitors reduced mHTT-induced death of rat striatal neurons and induced pluripotent stem cells derived from HD patients.

The study provides converging genetic and pharmacological evidence that reduction of ATM signaling could ameliorate mHTT toxicity in cellular and animal models of HD, suggesting that ATM may be a useful therapeutic target for HD.

Source; Science Magazine

In a guest post, Prof. Elena Cattaneo, University of Milan, Italy reports in EUROSTEMCELL on recent research that examines how a particular type of cell develops in the human brain, and how studies like this fit into the overall picture of research collaboration and funding, in Italy and in Europe.

The striatum is the area of the brain that degenerates in Huntington’s disease (HD) – a neurodegenerative disorder that as of today, has no cure. It took 4 years of continuous experiments of 17 researchers from 6 groups in 2 European countries to understand more about how cells develop in the striatum. This work, led by the group at the University of Milan, was published in Nature Neuroscience on 10 Nov 2014.

According to Prof. Cattaneo, “this kind of study is important because we need to understand more about how our tissues and our cells develop in order to understand why they degenerate. This will also allow us to build strategies to slow the advancement or prevent the onset of disease“.

We identified how striatal neurons mature in the human brain, at a molecular and functional level. These neurons are the ones that die in Huntington’s disease. During the earlier stages of the development of the brain, stem cells are found in an area just around the ventricles. Stem cells destined to generate the striatal neurons possess an identifying molecular code, which then turns into a second code acquired by the cells when they move from this location en route to the striatum. Then, a third identifying code is acquired when the cells finally reach the striatum, where they will remain.  For the first time, we could study these 3 steps in development, working with post mortem tissue”

Source:  EuroStemCell website

In the first post on this new online service, Dr Ed Wild and Dr Jeff Carroll talk about the five new clinical trials enrolling now or starting soon for Huntington’s disease. Plus, a detailed discussion of the eagerly-awaited clinical trial of the first ‘huntingtin lowering’ drug to be tested in Huntington’s diease. Called HTT-Rx, the drug is an antisense oligonucleotide developed by Isis Pharmaceuticals Inc.

The 2CARE study of coenzyme Q for Huntington’s disease was halted early because an analysis of the results to date showed that it was very unlikely to show positive results. The study, called 2CARE, was designed to test whether a treatment called coenzyme Q10 could slow the progression of HD.