RE1/NRSE Mediated Gene Transcription

HD Lighthouse Contributing Editor's Comment:

Here is another major advance in our understanding of Huntington's Disease. The research reported here is beautifully done, builds on the cumulative work of this research team, and identifies an early pathology in HD which is targetable by either a drug or gene therapy. I would put the importance of this research alongside the molecular zip code research and the caspase 6 research.

Research by Dr. Cattaneo and colleagues and other research teams has shown that gene transcription is impaired in Huntington's Disease. DNA is a blueprint for life, but it has to be read and instructions have to go out for the work to be done. Gene transcription is the 'reading' of the DNA code and RNA is the messenger which carries the instructions which are read.

The normal huntingtin protein is associated with the transcription of the gene for BDNF (brain derived neurotrophic factor). The HD version is associated with the reduction of BDNF and that reduction is clearly a major pathology of the disease. HDlighthouse readers are already well aware of this reduction and are exercising and/or taking SSRI antidepressants to try to boost BDNF levels.

This study identifies just exactly how that reduction happens. The normal huntingtin protein stimulates the transcription of the BDNF gene through the activation of the repressor element 1/neuron-restrictive silencer element (RE1/NRSE) on the BDNF promoter. There is a transcription factor called the RE1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) which will silence the BDNF gene if the transcription factor is not sequestered in the cytoplasm of the cell by the normal huntingtin protein. Remember though, that the HD version of the protein accumulates in the nucleus of the cell. As it does so, REST/NRSF also accumulates and represses gene transcription.

And it isn't just the BDNF gene that is suppressed. There are a number of other genes which are suppressed which may explain the variety of pathological cellular processes associated with Huntington's Disease. The researchers list 42 of these which are involved in neuronal development, signaling, synaptic transmission, transport, transcription, metabolism, immune system response, spermatogenesis. Some of the functions of the suppressed genes are still unknown.

The researchers then attempted to restore gene transcription. In this study, they introduced a dominant negative REST/NRSE construct into an HD knock in cell through the use of a viral vector and found that gene expression was restored within 48 hours. This suggests that gene therapy could be an effective treatment for Huntington's Disease.

In a subsequent study (referenced below) which will be covered by the Lighthouse later, Cattaneo and colleagues did a cell based essay to find a compound which would upregulate the genes. They found three which did so, one of which increases the viability of the cell. This suggests that upregulation of the suppressed genes would be a good target for drug discovery or development.

Reference

Dorotea Rigamonti, Daniele Bolognini, Cesare Mutti, Chiara Zuccato, Marzia Tartari, Francesco Sola, Marta Valenza, Aleksey G. Kazantsev, and Elena Cattaneo. "The Loss of Huntingtin Function Complemented by the Loss of Small Molecules Acting as Repressor Element 1/Neuron Restrictive Silencer Element Silencer Modulators." J. Biol. Chem., Vol. 282, Issue 34, 24554-24562, August 24, 2007

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 25 Aug 2007

Dr. Elena Cattaneo at a recent Hereditary Disease Foundation conference.

New Hope for Huntington's sufferers

A major breakthrough in the understanding and potential treatment of Huntington's disease has been made by scientists at the University of Leeds .

Researchers in the University's Faculty of Biological Sciences have discovered that one of the body's naturally occurring proteins is preventing 57 genes from operating normally in the brains of Huntington's sufferers. In addition, the destructive nature of this protein could potentially be halted using drugs that are already being used to help cancer patients.

“This is a really exciting breakthrough,” says researcher Dr Lezanne Ooi. “It's early days, but we believe our research could lead to radical changes in treatment for Huntington's sufferers. The fact that these cancer drugs have already been through the clinical trials process should speed up the time it takes for this research to impact directly on patients.”

Huntington's is an inherited degenerative neurological disease that affects between 6500 and 8000 people in the UK and up to 8 people out of every 100,000 in Western countries. Any person whose parent has Huntington 's has a 50-50 chance of inheriting the faulty gene that causes it and everyone with the defective gene will, at some point, develop the disease.

It is characterised by a loss of neurons in certain regions of the brain and progressively affects a sufferer's cognition, personality and motor skills. In its later stages, sufferers almost certainly require continual nursing care. Secondary diseases, such as pneumonia are the actual cause of death, rather than the disease itself.

Dr Ooi's research has identified the effects of one of the body's proteins on the neurons of Huntington 's sufferers. Neurons are usually protected by the protein BDNF (brain derived neurotrophic factor), whose many functions also include encouraging the growth and differentiation of new neurons and synapses. However, in Huntington 's sufferers, the repressor protein known as REST - which is usually found only in certain regions of the brain - enters the nucleus of the neuron and decreases the expression of BDNF.

She has also been studying some of the enzymes which assist the function of this protein. It is these enzymes that provide the mechanism for the protein to wreak havoc in the brains of Huntington's sufferers, and that are already being targeted in certain cancer drugs.

Currently, the symptoms of Huntington's can be managed through medication to help with loss of motor control and speech therapy but there is no definitive treatment. This research provides a first step in developing a treatment regime that may halt the onset of the disease.

“Huntington's is a devastating illness that affects whole families. Those who know they've inherited the faulty gene live in a shadow of uncertainty over how long their symptoms start to develop. It can also be particularly cruel since every child born to a parent that has the HD gene is at 50% risk of having inherited the gene,” says Cath Stanley, Head of Care Services at the Huntington's Disease Association.

“As such, any developments in the understanding of this disease are welcome, but this breakthrough is particularly exciting as it opens up an avenue for researching a possible treatment using drugs that are already available, rather than starting from scratch.”

Dr Ooi's research was funded by The Wellcome Trust and carried out in collaboration with the University of Milan and King's College London. The paper has been published in the Journal of Neuroscience.

the journal abstract

Huntingtin is a protein that is mutated in Huntington's disease (HD), a dominant inherited neurodegenerative disorder. We previously proposed that, in addition to the gained toxic activity of the mutant protein, selective molecular dysfunctions in HD may represent the consequences of the loss of wild-type protein activity. We first reported that wild-type huntingtin positively affects the transcription of the brain-derived neurotrophic factor (BDNF) gene, a cortically derived survival factor for the striatal neurons that are mainly affected in the disease. Mutation in huntingtin decreases BDNF gene transcription. One mechanism involves the activation of repressor element 1/neuron-restrictive silencer element (RE1/NRSE) located within the BDNF promoter. We now show that increased binding of the RE1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) repressor occurs at multiple genomic RE1/NRSE loci in HD cells, in animal models, and in postmortem brains, resulting in a decrease of RE1/NRSE-mediated gene transcription. The same molecular phenotype is produced in cells and brain tissue depleted of endogenous huntingtin, thereby directly validating the loss-of-function hypothesis of HD. Through a ChIP (chromatin immunoprecipitation)-on-chip approach, we examined occupancy of multiple REST/NRSF target genes in the postmortem HD brain, providing the first example of the application of this technology to neurodegenerative diseases. Finally, we show that attenuation of REST/NRSF binding restores BDNF levels, suggesting that relief of REST/NRSF mediated repression can restore aberrant neuronal gene transcription in HD.

Source: The Journal of Neuroscience, June 27, 2007, 27(26):6972-6983

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