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Neurobiology
Immune Proteins Found Moonlighting in Brain
A pair of fuzzy-brained mice is providing tenet-toppling clues to one of the great puzzles in neuroscience: how do the finely wrought neural patterns of the brain emerge from a hodgepodge of early connections?
"It has to be seriously considered now that in brain cells undergoing degeneration there is a possibility that the neurons are being targeted for destruction by the immune system," said Carla Shatz (left), shown with co-authors Gene Huh and Lisa Boulanger, research fellow in neurobiology. Photo by Pam Murray
The mutant mice, studied by HMS researchers, are also offering tantalizing clues to neurological mysteries such as how might developmental disorders like dyslexia arise? What triggers the killing of neurons in Parkinson's disease and other neurodegenerative disorders?
While the brain's early scaffolding of connections is determined strictly by genetic instructions, the refashioning that occurs during development—and in learning—is a product of both genes and the brain's own activity. Yet neuroscientists have come up mostly empty-handed in their quest to identify the molecular artisans responsible for this activity-dependent remodeling.
Gene Huh, Carla Shatz, and their colleagues have recently pulled a pair of candidates from an unlikely pool—the immune system. They found that mice lacking one of two immune proteins, Class I MHC and CD3-zeta, failed to undergo remodeling in a visual area of the brain, the lateral geniculate nucleus. The mice also experienced abnormal functioning in a region of the brain associated with learning, the hippocampus, the researchers report in the Dec. 15 Science.
In the immune system Class I MHC and CD3-zeta act as part of a lock and key system for recognizing and getting rid of foreign invaders. At left, Class I MHC (pink) presents foreign antigens to the T cell receptor (TCR), which contains CD3-zeta (red). In the brain, at right, Class I MHC may interact with an unknown receptor (circle), which contains CD3-zeta, part of a signaling system that recognizes and eliminates inappropriate connections. Adapted from original by Gene Huh
In the immune system, Class I MHC and CD3-zeta act as part of a lock and key system to recognize and rid the body of foreign invaders. In the brain, they may be part of a signaling system that recognizes and eliminates inappropriate connections, says Shatz, the Nathan Marsh Pusey professor and chair of neurobiology at HMS.
Though evidence is still sketchy, Shatz believes defects in the Class I MHC and CD3-zeta remodelers could play a role in dyslexia. "If you do MRI and look at the brain of a person with dyslexia, it looks perfectly normal. There's nothing structurally weird about the brain," she said. "But it is possible that if you look at the detailed connections, they would be funny."
The presence of MHC Class I prompts another speculation: that neurodegenerative diseases such as multiple sclerosis and Parkinson's may be the consequence of a misguided attack by immune cells on Class I MHC-bearing neurons. "MHC Class I-bearing neurons could be the target for an abnormal immune response. I think that people need to start thinking about that," Shatz said.
—Misia Landau
