Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Chemical chaperone could open door to treatment of neurological disorder

07.02.2008
An unexpected finding turned out to be a clue leading researchers at Washington University School of Medicine in St. Louis to propose a new treatment approach for Niemann-Pick disease, a rare, deadly neurodegenerative disorder.

To overcome the genetic defect in Niemann-Pick disease, the researchers suggest that chemical compounds could potentially "chaperone" mutant protein molecules through the cell's quality control machinery. And they believe the approach also could be useful for more common diseases — such as cystic fibrosis — that stem from a similar type of defect.

Their findings are reported in advance online publication in the Journal of Biological Chemistry.

Daniel S. Ory, M.D., associate professor of medicine, and colleagues in the Center for Cardiovascular Research originally began to study Niemann-Pick type C disease because of its link to cholesterol metabolism — the genetic abnormality at the root of the disease serves as a tool for investigating how cholesterol moves about in cells.

Niemann-Pick type C, the rarest form of Niemann-Pick disease, usually affects school-aged children, but the disease may occur at any time from early infancy to adulthood. Symptoms may include unsteadiness of gait, clumsiness, slurred speech, learning difficulties, progressive intellectual decline, seizures and tremors. Niemann-Pick type C disease is fatal, and no life-extending treatment exists.

As the result of their latest research, Ory and colleagues want to follow up with an investigation of a different treatment modality than has previously been proposed. Prior avenues of treatment research emphasized using gene therapy to repair the genetic defect, but such an approach is fraught with numerous difficulties. Ory's group believes that Niemann-Pick type C and other diseases like it might be treated more readily with chemical compounds able to compensate for the effect of the disease's underlying genetic mutation.

Niemann-Pick type C disease is a recessive inherited trait that can originate in one of more than 200 different mutations in the NPC1 gene, which lies on chromosome 18. The mutations lead to production of abnormal NPC1 protein. Normally, NPC1 protein plays an essential role in moving cholesterol out of cells, and if it doesn't function, cholesterol and other lipids accumulate.

Most scientists assumed that Niemann-Pick type C mutations produced NPC1 protein that didn't work correctly. So when a routine test in the Ory lab of a mutated NPC1 protein showed that the protein was in fact active in living cells, the researchers did a double take.

"It is unequivocal that the mutation causes disease in human patients," says Ory, also associate professor of cell biology and physiology. "Yet the mutated protein seemed functional when we introduced it into cells."

When they looked for the explanation for this aberration, Ory and colleagues found that a small proportion of the mutant protein actually could do the job of normal NPC1 protein. It turned out that the mutation caused most newly minted NPC1 protein molecules to fold into the wrong shape or to assume their final shape slowly so that the cell's quality control checkpoints rejected them. But some of the mutant protein molecules assumed the correct shape and made it to their proper destination.

That suggested to the team that Niemann-Pick type C disease possibly could be treated with chemicals that assist the mutant proteins produced in patients. Ory refers to these as chemical chaperones and indicates this approach could help the large NPC1 proteins during the process of folding their long, complex chains so that more of the mutant proteins fold properly and pass through the cell's quality control checkpoints.

In collaboration with the National Institutes of Health Chemical Genomics Center, Ory will next screen more than 200,000 compounds to see which ones increase the amount of mutant NPC1 that folds into a functional form.

"The screening can be done in as little as two weeks because the facility in Rockville, Md., has a huge library of compounds and state-of-the-art robotic equipment that can perform the tests at very high speed," Ory explains. "Then we will bring the compounds that show a positive effect to our laboratory and validate them on cell lines from Niemann-Pick patients. After that we will work with a pharmaceutical partner to take the ones that are effective in cells and make sure they will be safe and effective in people."

Although Niemann-Pick disorders are rare, affecting fewer than 2,000 people worldwide, Ory says that it is likely the chemical chaperone approach to therapy could also be useful for other disorders caused by genetic mutations that lead to protein misfolding. This includes cystic fibrosis, a lung and digestive system disorder that affects 70,000 children and adults around the world.

Gwen Ericson | EurekAlert!
Further information:
http://www.wustl.edu

Further reports about: Genetic Mutation NPC1 Niemann-Pick Ory chaperone cholesterol compounds

More articles from Life Sciences:

nachricht Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel

nachricht The Nagoya Protocol Creates Disadvantages for Many Countries when Applied to Microorganisms
05.12.2016 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

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...

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

IHP presents the fastest silicon-based transistor in the world

05.12.2016 | Power and Electrical Engineering

InLight study: insights into chemical processes using light

05.12.2016 | Materials Sciences

High-precision magnetic field sensing

05.12.2016 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>