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 Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University

nachricht The first analysis of Ewing's sarcoma methyloma opens doors to new treatments
01.12.2016 | IDIBELL-Bellvitge Biomedical Research Institute

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: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>