Sci. Aging Knowl. Environ., 6 February 2002
Vol. 2002, Issue 5, p. nf3
[DOI: 10.1126/sageke.2002.5.nf3]


Age Discrimination

Mitch Leslie;2002/5/nf3

Take a gleaming new Porsche Boxster. Leave it outside during hailstorms. Let road salt gnaw the paint and body. Don't change the oil even after it congeals into lumpy tar, shun tune-ups, and never lube the chassis. What do you have after a few years? A pricey heap that looks and runs like a 1975 AMC Gremlin. What's true of cars is also true of the cells in the nervous system, according to a new study of knockout mice. Even with the best attention during manufacturing, neurons degenerate with age unless properly maintained. The findings emphasize the importance of upkeep for long-term functioning of neurons.

Neuroscientists praise the study for clarifying the function of an enigmatic gene that could cause or accelerate neurodegenerative diseases. The results might get people thinking about what triggers some unexplained types of nerve degeneration that trouble the elderly, says Gunnar Gouras, a neurologist and neuroscientist at Cornell Medical College in New York City.

The results emerge from research on mice that lack the stathmin gene, which has starred in many recent studies of cancer, cell cycle regulation, and embryonic development. Scientists probably haven't yet discovered all of stathmin's jobs, but they know it helps regulate the structure of microtubules within cells, says molecular neuroscientist Wolfgang Liedtke of Rockefeller University in New York City, an author of the new paper. These hollow, straight protein rods shepherd the chromosomes to opposite ends of the cell prior to division, help haul organelles and cellular cargo around, and form part of the cell's internal skeleton. Previous work established that stathmin speeds the breakdown of microtubules. Although this ability might seem harmful, rapid turnover is normal for microtubules. Like a circus tent, they are continually being disassembled and reassembled.

Production of the stathmin protein booms during embryonic development, and the sequence of the gene has changed little over evolutionary time. Both observations suggest that stathmin is vital and that losing it would foul up a developing embryo, says Liedtke. But scientists led by Ulrich Schubart of the Albert Einstein College of Medicine in New York City found otherwise when they created stathmin knockout mice in 1996. To everyone's surprise, the rodents grew into healthy, fertile, beady-eyed adults that scurried about normally.

However, the researchers followed the knockout animals for only 2 months after birth. When Ulrich, Liedtke, and colleagues undertook a longer study of the same strain, they discovered progressive and widespread deterioration of the nervous system, beginning when the creatures were middle-aged. The abnormalities appeared in axons, the long, snaky extensions that allow a neuron to link up to other nerve cells and muscles. Normally, an axon's contents and skeletal supports are distributed regularly. But in the knockout mice, the contents look uneven, clumped in some places and diffuse in others, while the strands of the skeleton pack together (see figure). The damage worsens with age. The insulating myelin sheath around the axon often erodes, and some axons begin to disintegrate. Injured axons show up only in the motor tracts of the spinal cord, which relay messages from the brain to the muscles, in the optic nerve, and in the peripheral nerves. The brain and the rest of the spinal cord seem to be spared. Eliminating a protein that normally destabilizes microtubules would logically bolster the cell's internal framework, and researchers aren't sure why deleting stathmin instead causes nerves to fall apart. Perhaps, Liedtke suggests, stathmin has functions in addition to dissolving microtubules.

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Falling apart. An axon shows early signs of internal disorganization (left). At a later stage (right), the strands of the cell's skeleton have compacted, and the myelin sheath has begun to disintegrate. A macrophage, a type of immune cell, has slipped into the gap left by the shrinking axon. [Credit: W. Liedtke and Cedric Raine]

Oddly enough, the mice still seemed hale, despite their crumbling nerves. For example, they walked and groomed themselves normally. To determine whether the deterioration had functional consequences, the researchers measured the speed of nerve impulses in old normal and stathmin-deficient mice. The impulses traveled 22% slower in the knockouts. The rodents might not have griped, but "a person with equivalent changes might complain about weakness, inability to walk long distances, and perhaps pain," says Liedtke.

Like previous work on stathmin, the study presents some puzzles. For one, why do the ill effects of losing the gene take so long to appear? Liedtke proposes that related genes might temporarily compensate for its absence. The stathmin gene belongs to a family of four with similar structures and presumably similar functions, says Liedtke. The researchers found that the activity of one of these genes, known as SCLIP, was high in the brain and higher in the spinal cords of old knockout mice.

A bigger question is whether mutations in the gene exert similar effects on the human nervous system. You won't find stathmin deficiency in any textbook of neurological disorders, and the mice developed no apparent symptoms. To neuropathologist Dennis Dickson of the Mayo Clinic in Jacksonville, Florida, that observation suggests that stathmin probably has no clinical importance. However, Liedtke thinks that stathmin defects might underlie some nerve disorders of the elderly. Gouras agrees and points out that cases of unexplained neuropathy, or nerve degeneration, are fairly common among older patients.

Furthermore, the seeming lack of physical symptoms in the mice despite significant neurological damage might correspond to a common stage of human disorders, says neuroscientist Bruce Trapp of the Cleveland Clinic in Ohio: "Almost all neurodegenerative diseases start with a long, silent phase." By the time people with Parkinson's disease get to the doctor's office, for example, they have already lost about 80% of their dopamine-producing neurons, he says. Perhaps the knockouts are in that phase. And the findings raise another possibility, Trapp adds. Rather than causing disease directly, a lack of stathmin might speed the progression of neurodegenerative diseases such as multiple sclerosis or amyotrophic lateral sclerosis. Such a scenario could explain why progression of these diseases races in some patients and dawdles in others.

The biased attention that stathmin pays to older neurons could stimulate more interest in how neurons stay alive over the long haul, says Liedtke. Many neuroscientists have devoted their careers to understanding how genes guide young neurons to the proper positions, but they have paid little attention to the genes and proteins that keep cells alive and working after growth is finished. Yet, this maintenance is equally important to an efficient nervous system, Liedtke says. Unlike cars, most neurons have to last a human lifetime.

February 6, 2002

Mitch Leslie writes for SAGE KE from Albuquerque, New Mexico. He is disappointed that his neurons didn't come with a warranty, and he is reconsidering the wisdom of putting any strain on his brain.

Suggested ReadingBack to Top

  • W. Liedtke, E. Leman, R. Fyffe, C. Raine, U. Schubart, Stathmin-deficient mice develop an age-dependent axonopathy of the central and peripheral nervous systems. Am. J. Pathol. 160, 469-480 (2002). (Issue is expected to go online 11 February.) [Abstract] [Full Text]
  • U. K. Schubart, J. Yu, J. A. Amat, Z. Wang, M. K. Hoffmann, W. Edelmann, Normal development of mice lacking metablastin (P19), a phosphoprotein implicated in cell cycle regulation. J. Biol. Chem. 271, 14062-14066 (1996). [Abstract] [Full Text]

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