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February 17, 2006
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Protein May Also Be Linked to Autism and Other Disorders
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Independent research teams from Harvard Medical School and Children's Hospital Boston have identified a master protein that sheds light on one of neurobiology's biggest mysteries-how neurons change as a result of individual experiences. The research, which appears in two papers in the latest issue of Science (Feb 17), identifies a central protein that regulates the growth and pruning of neurons throughout life in response to environmental stimuli. This protein, and the molecular pathway it guides, could help investigators understand the process of learning and memory, as well as lead to new therapies for diseases in which synapses either fail to form or run rampant, such as autism, neurodegenerative diseases, and psychiatric disorders.
Though axons and dendrites can be easily spotted waxing and waning under the microscope, the molecular middlemen working inside the cell to shape the neuron's sinewy processes have been much more elusive. The teams found a protein that works in the nucleus of neurons that either pares down or promotes synapses depending on whether or not the neuron is being activated. The protein, myocyte enhancer factor 2 (MEF2), turns on and off genes that control dendritic remodeling. In addition, one of the teams has identified how MEF2 switches from one program to the other, that is, from dendrite-promoting to dendrite-pruning, and the researchers have identified some of MEF2's targets.
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| Michael Greenberg, PhD, Harvard Medical School Professor of Neurology at Children's Hospital Boston |
The uncovering of the MEF2 pathway and its genetic switch helps fill in a theoretical blank in neurobiology, but what excites the researchers are the potential implications for the clinic. Michael Greenberg, PhD, Director of Neuroscience at Children's Hospital Boston, whose team authored one of the two papers, believes that the MEF2 pathway could play a role in autism and other neurodevelopmental diseases. "Changes in the morphology of synapses could turn out to be very important in a whole host of diseases including neurodegenerative as well as psychiatric disorders," adds Azad Bonni, MD, PhD, HMS Associate Professor of Pathology who, with colleagues, led the other team.
The protein works by either activating or actively repressing target genes. Steven Flavell, a graduate student in neurology, Greenberg, and their colleagues found the MEF2 activator inhibited the growth of dendritic spines -- the protrusions from dendrites where synapses form -- in the rat hippocampus, an area of the brain associated with memory and learning. Working on a group of neurons in the developing rat cerebellum, HMS research fellow in pathology Aryaman Shalizi, and HST medical student Brice Gaudilliere along with Bonni and their colleagues, found the MEF2 repressor promoted synaptic differentiation. Flavell, and the Bonni team also found that the activated, or dendrite-whittling, form of MEF2 comes on in response to increased neuronal activity.
That MEF2 activation leads to the inhibition of synapse formation, makes sense in light of what is known about the nervous system. In memory and learning, as well as development, activity leads to a sculpting, or cutting away, of synapses. What may be more surprising is the way activity causes MEF2 to switch from repressor to activator.
What Bonni and his colleagues found is that molecules modify a particular spot on MEF2, and transform it into a repressor. By removing the modification, known as sumoylation, MEF2 becomes an activator.
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MEF2 was first identified in neurons in the 1990s. In 1999, Zixu Mao, then an HMS research fellow, working with Bonni, Greenberg, and colleagues showed that MEF2 promotes neuronal survival but little else was known about the protein. Though they knew that MEF2 comes in activated and repressor forms, neither team knew how exactly the protein works. They suspected it might play a role in regulating activity-dependent synaptic remodeling and set out to find out if that was the case.
Taken together, the findings of the two groups might appear puzzling for they seem to say that MEF2 promotes synapse formation by repressing genes and suppresses synapse formation by activating genes. The puzzle resolves itself when one considers the possibility that the genes being turned on and off act to discourage synapse formation. In fact, Flavell and his colleagues have identified two of MEF2's targets, arc and SynGAP. The arc protein appears to play a role in internalizing glutamate receptors, which occurs when dendrites are being disassembled. SynGAP works to turn off the synapse-promoting ras gene. Bonni and his colleagues have identified yet a third target, Nur77. There are bound to be others.
The identification of these targets, and more generally the opening up of the MEF2 pathway, could lead to new therapies for a host of diseases in which synapses either fail to form or run rampant. In fact, Greenberg is currently a member of a consortium that is trying to get at the molecular underpinnings of autism. "We think the MEF2 pathway may be central," he said.
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To read a related press release on Greenberg's research on synapse development, visit: http://www.childrenshospital.org/newsroom/Site1339/mainpageS1339P1sublevel183.html
More information about Greenberg's laboratory is available online at: http://www.childrenshospital.org/cfapps/research/data_admin/Site159/mainpageS159P0.html
For further information:
Aaron Patnode
Children's Hospital Boston
617-355-6420
aaron.patnode@childrens.harvard.edu
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, nine members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 347-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: http://www.childrenshospital.org/research/.
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