Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Jefferson and Michigan Scientists Identify Gene Defect Behind Muscle-Wasting Disease

13.10.2003


Insights gained from extensive studies in mice may someday lead to treatments for comparable neurodegenerative diseases in humans



Scientists at Jefferson Medical College and the University of Michigan have uncovered a gene defect responsible for a muscle-wasting, neurodegenerative disease in mice known as mnd2. Their results may provide insights into the molecular origins of other such diseases in humans, including Parkinson’s disease.

In an online report on October 8 in the journal Nature, the researchers, led by Emad Alnemri, Ph.D., at Jefferson Medical College of Thomas Jefferson University in Philadelphia, and Miriam Meisler, Ph.D., at the University of Michigan in Ann Arbor, showed that a mutation in a single amino acid in the protein Omi/HtrA2 is enough to cause the neuromuscular disease. In mnd2 mice, the amino acid serine is changed to cysteine.


Michigan senior research associate Julie Jones, a member of Dr. Meisler’s research team, discovered the mnd2 mouse model, an inherited neurological disease, in 1990. mnd2 is characterized by an abnormal gait, muscle wasting and early death. To identify the guilty gene, Dr. Meisler’s laboratory used a technique called positional cloning, eventually narrowing the mutation to a small region containing six candidate genes on chromosome 6. To find the specific genetic defect, they determined the nucleotide sequence of these candidate genes and discovered that the mnd2 defect was caused by a “point” mutation in the Omi gene.

Dr. Alnemri had been studying the Omi/HtrA2 protease – an enzyme that cleaves proteins – and its role in programmed cell death. When he located the Omi gene on chromosome 2p13.1 – which happened to correspond to mouse chromosome 6, where the mnd2 locus is found – he suspected that a mutation in the Omi/HtrA2 gene could be behind the mnd2 disease. According to Dr. Alnemri, who is professor of microbiology and immunology at Jefferson Medical College and a member of Jefferson’s Kimmel Cancer Center, Omi/HtrA2 is present in the mitochondria, which generates energy in the cell. Omi regulates apoptosis, or programmed cell death, by binding and cleaving proteins that block the process. He and his co-workers at Jefferson characterized the mutation and discovered that it causes a loss of proteolytic activity of the protein, though the mutant protease can still bind to apoptosis-blocking proteins.

The Jefferson team performed additional tests on both normal and mutant mice cells, revealing that the cells from mutant mice were more sensitive to cellular stresses. They also discovered that mitochondria are defective in these cells as well. “The normal protease helps maintain normal mitochondrial function and is important for maintaining survival of cells in the nervous system,” says Dr. Alnemri.

The finding was surprising, says Dr. Meisler, a professor in the Department of Human Genetics at Michigan, because “Omi had not been thought to be involved in neurological disease. It appears to cause neuronal cell death by impairment of mitochondrial function.” “Interestingly, that same chromosome region in humans has been mapped in certain patients with Parkinson’s disease,” Dr. Alnemri notes. “We tested a few of these Parkinson’s samples but we did not find mutations in Omi. We still don’t know if this gene is mutated in other types of Parkinson’s or different neurodegenerative disorders.”

“Based on the severe neurodegeneration and muscle wasting in the mnd2 mouse, we will now begin to screen DNA samples from patients with related disorders in order to determine the medical impact of mutations in this gene,” says Dr. Meisler. “The prospects for treatment will be improved by accurate diagnosis in affected patients. We will extend the mutation search to the human gene, in order to determine its role in neuromuscular diseases.”

The Omi protein and related proteins are found in all organisms, including bacteria. In the latter, Omi-related proteins function as “molecular sensors” of cellular stresses, Dr. Alnemri says.

“Our next step is to find out whether Omi in humans functions as a sensor of mitochondrial stress and to understand at the molecular level how Omi regulates mitochondrial function,” he says.

Steven Benowitz | TJUH
Further information:
http://www.jeffersonhospital.org/news/e3front.dll?durki=17158

More articles from Health and Medicine:

nachricht Collagen nanofibrils in mammalian tissues get stronger with exercise
14.12.2018 | University of Illinois College of Engineering

nachricht New discoveries predict ability to forecast dementia from single molecule
12.12.2018 | UT Southwestern Medical Center

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: Data storage using individual molecules

Researchers from the University of Basel have reported a new method that allows the physical state of just a few atoms or molecules within a network to be controlled. It is based on the spontaneous self-organization of molecules into extensive networks with pores about one nanometer in size. In the journal ‘small’, the physicists reported on their investigations, which could be of particular importance for the development of new storage devices.

Around the world, researchers are attempting to shrink data storage devices to achieve as large a storage capacity in as small a space as possible. In almost...

Im Focus: Data use draining your battery? Tiny device to speed up memory while also saving power

The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.

Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...

Im Focus: An energy-efficient way to stay warm: Sew high-tech heating patches to your clothes

Personal patches could reduce energy waste in buildings, Rutgers-led study says

What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...

Im Focus: Lethal combination: Drug cocktail turns off the juice to cancer cells

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...

Im Focus: New Foldable Drone Flies through Narrow Holes in Rescue Missions

A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.

Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

 
Latest News

Pressure tuned magnetism paves the way for novel electronic devices

18.12.2018 | Materials Sciences

New type of low-energy nanolaser that shines in all directions

18.12.2018 | Physics and Astronomy

NASA research reveals Saturn is losing its rings at 'worst-case-scenario' rate

18.12.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>