The research involved a fly model of a rare human genetic disorder called ataxia-telangiectasia (A-T), but it may help explain the nerve-cell death that is the devastating common denominator in Alzheimer’s, Parkinson’s and Lou Gehrig’s diseases, among others.
Reduced ATM kinase activity in fruit fly glial cells causes expression of innate immune response genes. Green dots show the expression of genes related to the innate immune response, while the overalapping larger red dots show the location of glial cells.
“Our fly studies suggest that the early-onset neurodegeneration seen in A-T is similar to the late-onset neurodegeneration, characterized by uncontrolled inflammation, that is typical of diseases such as Alzheimer’s,” says Dr. David Wassarman, professor of cell and regenerative biology at the School of Medicine and Public Health.
The research showed that, contrary to expectation, the flies’ innate immune response was involved in the neurodegeneration in the A-T model flies. Its regular job is to provide an immediate defense against infection by producing inflammation and killing invading microorganisms.
“Our research has uncovered a new role for the innate immune system,” says Andrew J. Petersen, a Molecular and Cellular Pharmacology Program graduate student in Wassarman’s laboratory.
The experiments also showed that only certain nervous-system players – glial cells – were responsible for activating the innate immune response that caused nerve-cell death in flies modeling A-T. The glial cells became involved when the scientists reduced levels of a key protein shared by flies and humans, called ATM (A-T mutated) kinase.
Wassarman, Petersen and Dr. Stacey Rimkus, a former post-doctoral fellow in the lab, reported their findings recently in the Proceedings of the National Academy of Sciences.
The researchers wanted to understand why A-T causes nerve cells to die. They zeroed in on ATM kinase, which typically protects cells by recognizing DNA damage and recruiting proteins to repair it. Patients with A-T don’t have a functional ATM kinase gene, so any DNA damage that may occur in them usually cannot be repaired.
Petersen used a genetic technique to lower ATM kinase levels in the fly brain, essentially creating an A-T fly. ATM kinase deficiency reduced mobility and longevity in the animals and produced nerve-cell death. The researchers then conducted experiments to determine which underlying activities might account for the problems.
Unexpectedly, they found that lower levels of ATM turned on expression of genes involved in the innate immune response. It turned on these genes only in glial cells, the resident innate immune cells in the central nervous system.
“Activation of the innate immune response may be a common feature of neurodegeneration,” says Wassarman. “In diseases such as Alzheimer’s and Parkinson’s, neurotoxicity is thought to stem from prolonged activation of microglia, a version of glial cells. Uncontrolled inflammation may be at the heart of the neurodegeneration in numerous diseases.”
Wassarman and his team are now using their A-T flies to look for genes that inhibit the glial cell-stimulated innate immune response, and molecules that turn on the immune response. They’re testing FDA-approved drugs such as ibuprofen to see if inflammation can be prevented.
“Flies have been a great model for understanding human diseases for years,” Wassarman says. “I think they’ll tell us a lot about neurodegeneration.”
University of Wisconsin School of Medicine and Public Health