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NEUROSCIENCE Protector Protein Part of Nerve Cell DefenseBy Blocking Cell Death, Small Heat Shock Protein Might Counter Neurodegenerative Disease Nature's strategy for success is often excess--produce an abundance of sperm, for instance, in the hopes that one might successfully reach an egg. The nervous system develops in a similar vein: half of the neurons produced by vertebrate embryos die off before reaching their targets. This unusual overproduction may serve the same purpose as it does in procreation, by creating a competitive environment in which only the fittest survive. Not only are developing neurons vying for limited growth factors, they also succumb to death more easily when injured. But once the nervous system is more or less in place, the strategy shifts. It is now in the organism's best interest to keep its neurons in place or risk the kind of functional loss that comes with neurodegenerative disease.
Why do sensory and motor neurons become more resilient after development? Research by Clifford Woolf suggests that a heat shock protein helps buffer the mature cells from death after an injury. (Photo by Graham Ramsay) A study led by Clifford Woolf, the Richard J. Kitz professor of anesthesia research at Massachusetts General Hospital, suggests that a small heat shock protein, Hsp27, helps determine whether injured sensory and motor neurons live or die. The study, published in the Sept. 26 Neuron, suggests that the protein's protective effects in neurons may explain why adult neurons with axons in the peripheral nervous system survive and regrow after injury, while developing neurons quickly die off. Heat shock proteins are known to protect all cell types from various general assaults. They were originally discovered when cultured cells that were heated expressed the proteins at high levels and proved more resistant to other injuries and toxins. They help fold proteins that are misfolded in times of crisis, help maintain structural integrity of the cell, and serve as a counterbalance to apoptosis. But their specific role in the nervous system is not well known. Molecular Life LineA pantheon of factors holds sway over the lives of neurons, such as external growth factors and internal apoptotic and anti-apoptotic signals. This latest study shows that Hsp27 not only tips the balance in favor of survival when expressed in neurons, but also seems to be a sufficient and necessary factor for the cells to live.Woolf's team in the Neuroplasticity Research Group at MGH found that motor and sensory neurons in adult rats upregulate Hsp27 in its active phosphorylated form following injury to a peripheral nerve. In neonatal rats, however, the expression of Hsp27 is much lower following such injury, and only a tiny minority of those cells expressing the protein survive. There seemed to be an inverse relationship between the expression of Hsp27 and the expression of activated apoptotic factors and other signs of cell death. The team also found that they could mimic the behavior of adult cells in neonates, and vice versa, by adding or subtracting Hsp27. Delivery of Hsp27 into developing cells could mimic the hardiness of adult cells: after infecting neurons of neonatal rats with an adenovirus expressing human Hsp27, more of the neurons survived when the sciatic nerve was damaged. When the team deprived adult cells of Hsp27--using a herpes simplex virus encoding antisense Hsp27 to inhibit the protein's expression--they found that adult neurons began to die after nerve injury. Woolf's team determined that Hsp27 interacts with cytochrome c, a key signal in the apoptotic pathway. Cytochrome c activates a cascade of cell death proteins when released from the mitochondria. Hsp27 binds to the protein after its release and prevents it from triggering apoptosis. Cell Death PreventionThis mechanism explains how the change in Hsp27 expression over time plays a role in the development and refinement of the nervous system. "As part of neural development, many more neurons are made than needed. In order for that to work, the cells have to be able to die," Woolf said. "But in the adult, it's important to have as many survival tactics as possible. If damaged mature cells die, the effects are irreversible and functionally catastrophic."The finding raises the question of whether loss of Hsp27 might have a role in certain neurodegenerative diseases. And even if the protein is not a major factor in pathology, could it be used as a treatment? This year's Nobel Prize in medicine recognized the scientific and clinical importance of programmed cell death and the proteins that regulate it in normal development and disease. Many therapeutic strategies currently under investigation try to tip the balance of factors that promote or inhibit apoptosis. Hsp27 is being investigated as a target in cancer cells, where it helps protect carcinomas from death. Conversely, promoting its expression might be useful to prevent or treat neurodegeneration. The most obvious conditions that Hsp27 could benefit are degenerative diseases of motor neurons like amyotrophic lateral sclerosis and of sensory neurons like diabetic neuropathies and herpes zoster. Woolf noted that sensory and motor neurons responded equally to Hsp27, despite being very different kinds of cells. Hsp27's action in the cytoplasm against cytochrome c suggests that it could have a significant effect. "Since most apoptosis-inducing factors work upstream of it, Hsp27 may prove to be a powerful treatment," Woolf said. But the factors that regulate it are still unknown and must be investigated. --Courtney Humphries |
