Sci. Aging Knowl. Environ., 14 August 2002
Nerve growth factor invigorates mice with Lou Gehrig's disease
Key Words: motoneuron iNOS caspase-1 EAAT2 GLT1
Abstract: Rookie athletes sometimes fall short of fans' expectations; likewise, nerve growth factors haven't fulfilled their promise of preventing neurodegeneration. But the molecules might have broken out of their slump. An extra dose of one such protein slows neurodegeneration and extends life in mice with Lou Gehrig's disease, according to a new study. The research rekindles hope for nerve growth factor-based therapies.
Patients with amyotrophic lateral sclerosis (ALS; also called Lou Gehrig's disease, after the baseball star debilitated by it) lose motor neurons, suffer from tremors and paralysis, and eventually die from the affliction. ALS and its neurodegenerative cousins Parkinson's, Alzheimer's, and Huntington's diseases all raze nerves but act in different areas of the brain and spinal cord. Determining the reason that ALS-afflicted neurons die might lead to treatments for the disorder and reveal general principles of neurodegeneration.
For almost 2 decades, researchers have been examining whether proteins that stimulate nerve growth could slow neurodegeneration. The handful of attempts to alleviate human ALS by injecting the proteins failed, however. "Most biotech and pharmaceutical companies have given up on nerve growth factors [to treat ALS]," says neuroscientist Jeffrey Deitch of Drexel University in Philadelphia, Pennsylvania. But Sun and colleagues never surrendered. Several years ago, the researchers discovered that hepatocyte growth factor (HGF), a protein that nurtures liver cells, also fosters neuron growth in culture. They wondered if this protein might waylay the neuronal damage associated with ALS.
The team tested this idea on mice that mimic the disorder. These animals carry a mutation commonly found in ALS patients, which alters superoxide dismutase (SOD1), an enzyme that protects cells from oxidative stress (see "The Two Faces of Oxygen"). The researchers engineered the mutant mice to produce extra HGF in neurons. At 8 months of age, the rodents retained twice as many motor neurons as did ALS mice without auxiliary HGF. The difference translated into better living: The supplemented animals had 15% more time before paralysis hit and lived 12% longer.
To understand how HGF protected the mice, the researchers looked for physiological differences between treated and untreated animals. Extra HGF didn't prevent SOD1 aggregates in the spinal cord, a pathology that appears early in ALS. But the protein lowered the concentrations of a cell suicide-inducing enzyme that neurons manufacture midway through ALS progression; it also quashed production of an enzyme that manufactures destructive oxygen-containing molecules. Furthermore, HGF treatment elevated the amount of a protein that sucks neurotransmitters into cells, which usually drops late in the disease. According to co-author Hiroshi Funakoshi, a molecular neurobiologist at Osaka University in Japan, the results suggest that HGF intervenes after the early stage of ALS.
The study hints that nerve growth factors might hold therapeutic potential after all, says Deitch. The previous tests on ALS patients might have failed because the proteins didn't reach the motor neurons, he adds. Resolving that problem, perhaps by using an engineered virus that delivers proteins directly to target cells, might put nerve growth factors back in the lineup against neurodegenerative disease.
--Mary Beckman; suggested by Joy Goto
W. Sun, H. Funakoshi, and T. Nakamura, Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS. J. Neurosci. 22, 6537-6548 (2002). [Abstract] [Full text]
Citation: M. Beckman, Nerve Verve. Science's SAGE KE (14 August 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/32/nw113
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