Longevity Enzyme Protects the Brain
Delays degeneration of nerve cell communication lines
An enzyme linked to extended lifespans in a variety of organisms also appears to delay the degeneration of cable-like structures called axons that nerve cells use to communicate.
"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 Milbrandt. "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."
Previously, researchers had found that axon degeneration may be a process that neurons activate under certain conditions. They also found that an enzyme called Sirt1 seemed to block the process.
Sirt1 has received much attention for its apparent role in longevity. Part of the sirtuin family of enzymes, Sirt1 appears to be activated by the body in response to stressful conditions, helping cells survive.
Milbrandt and colleagues identified Sirt1's role in axon preservation by studying a strain of mutant mice known for the slowness with which their axons degenerate after injury.
The mice have a mutation that fuses together two proteins, Nmnat1 and Ufd2a. Nmnat1 stimulates the production of nicotinamide adenine dinucleotide (NAD),, a coenzyme that activates sirtuins. Ufd2a helps to assemble protein tags known as ubiquitins, which 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," says Milbrandt.
Hints from mutants
When Milbrandt and colleagues studied cultured neurons from the mutated mice, they found that in cells modified to make only Ufd2a, axons degenerated at a normal rate when damaged. Axons of neurons that made only Nmnat1, however, degenerated much more slowly under the same conditions.
The researchers found that a mutation that disabled Nmnat1's ability to synthesize NAD also disabled the protective effect, shifting their focus 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 [sirtuins] 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.
When the researchers shut down the activity of sirtuins, the protective effect disappeared, proving that their hunch was correct. This occurred even when the researchers administered extra NAD to the neurons several hours before injury, which had previously induced a protective effect.
Through a series of experiments, the researchers found that the protective effect seemed to be most strongly associated with Sirt1.
"The next step is to find out what genes Sirt1 is turning on and off that protect axons when the nerve cell is injured," says Milbrandt. "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."