Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A new pathway for halting neuronal death in Huntington’s disease

13.06.2002


The body is an extremely complex puzzle in which every piece plays a critical role. Should pieces disappear harmony is compromised. Such is the case with certain neurodegenerative diseases; when neurons suddenly die, the body’s ability to function properly is jeopardized.

CNRS (1) and INSERM biologists from the Curie Institute are working to understand how neurons die in one specific neurodegenerative disease: Huntington’s disease.
They have just announced the discovery of two new factors capable of blocking cell death induced in Huntington’s disease. They may eventually provide targets for the therapeutic treatment of this type of disease.
These discoveries were published in the 7th of June issue of Developmental Cell.



Huntington’s disease, also known as Huntington chorea, is a rare neurological disease that affects one in every 10,000 individuals. The disease’s most striking symptoms, which are usually manifested between the age of 35 and 50 years, include abnormal and involuntary jerky movements of the limbs, head and neck (chorea). Other symptoms include behavioral problems (anxiety, irritability, depression, etc.). As the disease progresses, a slow intellectual deterioration inevitably leads to dementia. Death occurs between 15 to 20 years after the onset of the disease, usually due to complications (pulmonary emboli, pneumonia, or similar infection).

Clinical diagnosis is often long and difficult to establish due to a wide range of symptoms that can easily be confused with other psychological disorders. Diagnosis should be confirmed by MRI scan of the brain or by genetic testing. If a family history of the disease can be established, predictive gene testing can be done on asymptomatic family members. However, this step must be thoughtfully considered beforehand as the disease’s initial symptoms appear relatively late, and at present, there is no treatment that can effectively delay the onset or the development of the disease.

A mutant protein: huntingtin

Huntington’s disease is an autosomal dominant genetic disorder: if one of two parents carry the mutant gene, 50% of their offspring will inherit the mutation and develop the disease.
The IT15 gene responsible for the disease, located on chromosome 4, enables the synthesis of the huntingtin protein, whose function has yet to be established. In its normal state, this protein contains repeated tracks of the amino acid glutamine. These repeats can become dangerous: if a threshold of 35 to 40 glutamines is exceeded, huntingtin becomes mutant and induces the disease. The more numerous the repeats, the earlier the symptoms appear.

It has been established that this abnormal expansion of glutamines is responsible for a change in the structure of huntingtin, which by some still poorly understood mechanism provokes neuronal cell death.

A number of other neurodegenerative diseases have also been linked to the same type of mutation. Different, specific regions of the brain are affected in each of these diseases. In Huntington’s disease, it is the striatum neurons (implicated in motor control), which gradually degenerate.

Under the direction of Frederic Saudou (2), a research team ("Intracellular signalling and neuronal death" UMR 146 CNRS/Institut Curie) studying Huntington‘s disease, has focused particular attention on the proteins suspected of playing a role in the neuronal death associated with this disease.

A model to understand neuronal death

To shed light on the mechanisms involved when neuronal death is induced by mutant huntingtin, researchers at the Curie Institute developed a cell model that reproduces the disease’s characteristics. The tool had already proved to be ideal as it allowed them to demonstrate that the huntingtin protein had to build up within the nucleus of the cell to induce neuronal death by apoptosis (3) (see “More information”).

Using the same tool, Sandrine Humbert (4), a member of Frederic Saudou’s team, has just demonstrated that the proteins IGF-1 and Akt (see “More information”) have a protective effect in the cellular model that reproduced the pathological symptoms.

Indeed, IGF-1 and Akt are capable of blocking both neuronal death and the formation of intranuclear aggregates within cells where the huntingtin protein is mutant (images available).

The researchers also discovered how the Akt protein "disrupts the plans" of mutant huntingtin: it chemically modifies it (via a mechanism known as phosphorylation), which leads to a change in both form and function. Once the huntingtin protein is altered by Akt, they noticed that aggregates no longer form in the nucleus and that apoptotic death is prevented. It is therefore a chemical modification that nullifies the negative effects of the mutant huntingtin protein inside the cells.

This is the first time factors that have a direct impact on the protein implicated in Huntington’s disease have been discovered.

Furthermore, Frederic Saudou’s team has demonstrated that the protein Akt has an abnormal appearance in patients suffering from Huntington‘s disease. This provides further proof, if any were needed, of the role of Akt in the development of this disease.

The IGF-1/Akt signaling pathway: a therapeutic turning point

Although these discoveries are still at a fundamental stage, they already point towards promising new treatments for Huntington’s disease. It is conceivable that the IGF-1 or Akt proteins may provide a therapeutic target for "deactivating" apoptosis, thus giving hope to all those afflicted with Huntington’s disease.

Eventually, research into treatments for other diseases like cancer, in which apoptosis plays a key role (see “More information”), may also benefit from these discoveries.


Notes
(1) Department of Live Sciences at the CNRS.
(2) Frederic Saudou is a research scientist at INSERM.
(3) Results published in the journal Cell in 1998 (95, p. 55-66), by Frederic Saudou.
(4) Sandrine Humbert is a research scientist at INSERM.

Images available at Curie press office


More information :


Requiem for a cell

In every living organism, cells grow, reproduce, and then die. But there are several ways they die. For example, when a cell is exposed to excessive stress or extreme temperatures (e.g. following a burn or abrasion), it ruptures and dies a violent death. The cell’s contents are widely dispersed, often leading to an inflammatory reaction. This accidental death is called "necrosis".

Apoptosis: programmed cell death

The cells can also "commit suicide," this is known as programmed cell death, or apoptosis. This form of cell death occurs throughout one’s life, beginning in the womb. In fact, apoptosis enables the embryo to develop and plays a role in the gradual growth of the body and its organs. Approximately 85% of the neuronal cells that grow inside the embryo’s brain are eventually eliminated. This "cleansing" is essential to prevent a surplus of brain cells that could prove detrimental to the proper function of the brain.
In addition to eliminating excess cells, apoptosis also rids the body of damaged cells that could prove harmful. Damage to a cell’s DNA can occur spontaneously or by exposure to a virus or the sun or various chemical compounds. Cells whose genetic material has been significantly altered are quickly eradicated to reduce or eliminate any risk of cancer.
When a cell is induced to commit suicide, it sets in motion a series of protein reactions that passes on this information and provokes various biochemical and morphological changes:
- A class of proteases, called caspases, cleave a certain number of proteins thus rendering them inactive;
- The nucleus shrinks and the DNA is degraded;
- The cytoplasm breaks into small round fragments;
- These fragments are then bundled by the dying cell’s outer membrane into small sacks that are subsequently ingested by neighboring cells.
On average, the process of apoptosis takes between 30 and 60 minutes for a single cell.

When apoptosis goes wrong

The slightest anomaly in this process can lead to serious problems for the entire body.
This is evidenced by a number of pathologies:
- When apoptosis is prevented, damaged cells are not eliminated, which enhances the risk of cancer.
- Similarly, an accelerated state of apoptosis, which would lead to the abnormal elimination of specific neurons, has been linked to certain neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.


Contacts


Institut Curie
Press office : Catherine Goupillon Tel + 33 1 44 32 40 63
Celine Giustranti Tel + 33 1 44 32 40 61
Iconography/secretary : Cecile Charre Tel + 33 1 44 32 40 51
service.presse@curie.fr
Fax + 33 1 44 32 41 67

CNRS
Press office: Martine Hasler Tel + 33 1 44 96 46 35
martine.hasler@cnrs-dir.fr
Fax + 33 1 44 96 49 93

INSERM
Press office: Nathalie Christophe Tel + 33 1 44 23 60 85
Séverine Ciancia Tel + 33 1 44 23 60 86
presse@inserm.fr

Catherine Goupillon | alfa
Further information:
http://www.cell.com

More articles from Health and Medicine:

nachricht NIST scientists discover how to switch liver cancer cell growth from 2-D to 3-D structures
17.11.2017 | National Institute of Standards and Technology (NIST)

nachricht High speed video recording precisely measures blood cell velocity
15.11.2017 | ITMO University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

Im Focus: Wrinkles give heat a jolt in pillared graphene

Rice University researchers test 3-D carbon nanostructures' thermal transport abilities

Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Antarctic landscape insights keep ice loss forecasts on the radar

20.11.2017 | Earth Sciences

Filling the gap: High-latitude volcanic eruptions also have global impact

20.11.2017 | Earth Sciences

Water world

20.11.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>