Molecular Basis of Oligodendrocyte Vulnerabilty and Impaired Regeneration with Age
2013 new Scholar Award in aging
The brain is a complex structure that intertwines neurons and glial cells. Evolution of the mammalian brain, in part, has been enabled by a class of glial cells, oligodendrocytes, which provide the myelin. Myelin sheaths wrap axons, the long, thin neuronal projections used to communicate with other neurons. Myelin enables neuronal signals to be transmitted more rapidly, and neuronal fibers to be connected to distant targets in a more organized way, with minimal volume expansion of the brain. Oligodendrocytes also provide metabolic and nutritional support for axons, and thus play critical roles in neuronal survival and integrity. Unfortunately, myelin can be easily damaged by a variety of pathological conditions, and stresses to the brain, and oligodendrocyte vulnerability to such damage is enhanced in the aged brain and in degenerative diseases. Extensive damage to white matter (myelin-rich brain areas) characterizes Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, pointing to myelin damage and oligodendrocyte impairment as a common path to the progression of these diseases, even though each of these diseases may have a different cause. If oligodendrocyte loss could be prevented or slowed during the course of neurodegenerative diseases, or if glial function in myelin-damage regions could be restored, disease-related decline in brain function might be prevented, slowed, or even reversed. The mammalian brain has a remarkable repair system due to abundant glial progenitor cells. In the healthy brain, stem cell-like glial progenitors can divide, migrate to an injured site, and become mature oligodendrocytes after myelin loss, but, unfortunately, the efficiency of remyelination declines with age. We propose that the age-related decline in the regenerative behavior of glial cells is caused by loss of cell-to-cell communication and changes in the internal gene expression of glia cells. My laboratory studies the molecular mechanisms underlying the enhanced vulnerability of oligodendrocytes in neurodegenerative diseases such as Alzheimer’s, including the age-related impairment of oligodendrocyte regeneration from glial progenitors. By determining how changes in gene expression affect the fate of glial cells in mice, we hope to understand the key factors that govern neural cell regeneration in the human brain. The results of our studies should identify potential mechanisms underlying the white matter abnormalities seen in many degenerative diseases, and may reveal novel therapeutic targets for regenerative medicine.