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Longevity Protein May Slow Many Neurodegenerative Disorders

Date:
August 16, 2004
Source:
Washington University School Of Medicine
Summary:
A protein linked to increased lifespan in yeast and worms also can delay the degeneration of ailing nerve cell branches, according to researchers at Washington University School of Medicine in St. Louis.

A protein linked to increased lifespan in yeast and worms also can delay the degeneration of ailing nerve cell branches, according to researchers at Washington University School of Medicine in St. Louis.

Scientists report in the Aug. 13 issue of Science that their findings might open the door to new ways to treat a wide range of neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), various kinds of neuropathy, and multiple sclerosis.

"It's becoming clear that nerve cell death in these disorders is often preceded by the degeneration and loss of axons, the branches of the cells that carry signals to the synapse," says senior investigator Jeffrey Milbrandt, M.D., professor of medicine and of pathology and immunology. "If this mechanism for delaying or preventing axonal degeneration after an injury proves to be something we can activate via genetic or pharmaceutical treatments, then we may be able to use it to delay or inhibit nerve cell death in neurodegenerative diseases."

Milbrandt and colleagues Toshiyuki Araki, M.D., Ph.D., research assistant professor of pathology and immunology, and Yo Sasaki, Ph.D., research associate, showed in mouse nerve cells that the protein SIRT1, which belongs to a family of proteins known as the Sir2 group, delays the breakdown of axons in nerve cells mechanically cut off from the cell body or exposed to a chemotherapeutic agent.

Scientists previously found evidence that this process of axonal degeneration may be an active self-destructive process that the neuron activates under certain conditions. Increased activation of SIRT1 appears to block some or all of those self-destructive processes.

Sir2 proteins previously have been linked to extended lifespans in yeast and the microscopic worm Caenorhabditis elegans. Scientists are also exploring the possibility of cancer prevention through drugs that increase the activation of Sir2 proteins.

Milbrandt's group was able to identify SIRT1's role in axon preservation through study of a mutant line of mice known for the slowness with which their nerve branches degenerate after injury. The mice have a mutation that fuses together parts of two proteins. One of these proteins, Nmnat1, stimulates the production of NAD, an essential component in cellular energy production. The other protein, Ufd2a, is involved in the assembly of protein tags known as ubiquitins that commonly label cell proteins for destruction.

"Mutations in proteins that regulate the addition of ubiquitins have been linked to some forms of Parkinson's disease, so we went into these experiments thinking that the ubiquitin assembly protein portion of the mutant protein was likely to be behind the protective effect," Milbrandt recalls.

However, when researchers studied cultured nerve cells carrying the mouse line's mutation, they learned otherwise. In cells genetically modified to make only the portion of Ufd2a found in the fused protein, nerve cell branches degenerated at normal rates when cut or exposed to a toxin. But branches in nerve cells that made only Nmnat1 had the protective effect, degenerating much more slowly under the same conditions.

Additional study showed a mutation that specifically disabled Nmnat1's ability to synthesize NAD also disabled the protective effect. This moved the focus of their hunt for the cause of the effect from Nmnat1 to NAD.

Efforts to further home in on the protective mechanism suggested that something affected by NAD in the cell nucleus was providing the protection.

"We decided to look at Sir2 proteins because they're activated by NAD, and once they've been activated they can turn on and off the activity of the genes for many other proteins," Milbrandt explains.

The hunch paid off: When they gave nerve cells a dose of Sirtinol, a drug that shuts down the activity of Sir2 proteins, the protective effect disappeared. This was true even though scientists had given extra NAD to the nerve cells several hours before they were injured, a step they had previously found could induce the protective effect.

Through a series of experiments, Araki and Sasaki found that the protective effect seemed to be most strongly associated with SIRT1, the first of seven Sir2 group proteins.

"The next step is to find out what genes SIRT1 is turning on and off that protect axons when the nerve cell is injured," Milbrandt says. "We'll also be looking at whether gene therapy approaches that increase these protective effects can delay disease in mouse models of human neurodegenerative disorders. We've already heard from a number of colleagues who are eager to give these pathways a try."

###

Araki T, Sasaki Y, Milbrandt J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science, Aug. 13, 2004.

Funding from the National Institute of Neurological Disorders and Stroke and the Alzheimer's Disease Research Center at Washington University.

Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked second in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.


Story Source:

The above story is based on materials provided by Washington University School Of Medicine. Note: Materials may be edited for content and length.


Cite This Page:

Washington University School Of Medicine. "Longevity Protein May Slow Many Neurodegenerative Disorders." ScienceDaily. ScienceDaily, 16 August 2004. <www.sciencedaily.com/releases/2004/08/040816090951.htm>.
Washington University School Of Medicine. (2004, August 16). Longevity Protein May Slow Many Neurodegenerative Disorders. ScienceDaily. Retrieved September 1, 2014 from www.sciencedaily.com/releases/2004/08/040816090951.htm
Washington University School Of Medicine. "Longevity Protein May Slow Many Neurodegenerative Disorders." ScienceDaily. www.sciencedaily.com/releases/2004/08/040816090951.htm (accessed September 1, 2014).

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