Protein holds promise for drug therapy for central nervous system diseases
Research shows that protein supports formation and survival of brain cells and promotes myelin repair
Researchers at UC Davis have identified previously unrecognized properties of a naturally occurring protein, finding that it enhances brain cell formation and survival and helps regenerate the protective covering around nerve cells, making it a "strong candidate" for drug development for people with diseases such as multiple sclerosis.
The protein, pigment epithelium-derived factor (PEDF), has well-known anti-tumor generating properties. But its role in promoting growth of a type of brain cell and regenerating the protective myelin sheaths around nerve cells had not been known, the researchers said.
"Our investigation found that PEDF plays a key role in accelerating regeneration of the myelin sheath," said study senior author David Pleasure, professor of neurology and pediatrics, and director of the Institute for Pediatric Regenerative Medicine, a collaborative initiative of the UC Davis School of Medicine and Shriners Hospitals for Children Northern California. "That makes PEDF a strong drug-therapy candidate, because it appears to encourage the regeneration of a type of brain cell called oligodendocyte and is able to repair the damage caused by demyelinative diseases, including MS."
Pleasure and his colleagues identified PEDF's functions on the adult central nervous system under both normal and pathological conditions in mouse-model research. The study was conducted in male and female wild-type mice that were continuously infused with a PEDF/saline suspension. Control mice received daily infusions of saline alone. The study found that in the PEDF infused mice, the PEDF receptor was expressed in various areas of the brain, including the corpus callosum and subventricular zone, reflecting the extensive effects of PEDF.
"What's unique about our findings is that we demonstrated that the continuous administration of recombinant PEDF into the normal adult mouse brain enhances production of glial cells in a critical portion of the brain," said Jiho Sohn, a post-doctoral scholar and lead study author. "In addition, we noted the maturation of oligodendrocyte progenitors in the bundle of nerve fibers that connect the left and right hemispheres of the brain." The study also documented that PEDF infusion enhances production of oligodendroglial progenitor cells from endogenous neural stem cells in mice with corpus callosum demyelinative lesions.
Multiple sclerosis is one of several disease conditions brought about by demyelination, or damage to the protective sheath around nerve cells. Demyelnation impairs the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition or other functions depending on which nerves are involved. Multiple sclerosis is believed to be caused by the body's immune system attacking the myelin coating on the nerves. There are more than 400,000 people in the United States with multiple sclerosis, for which there is no cure.
The study, "PEDF is a novel oligodendrogenic morphogen acting on the adult SVZ (subventricular zone) and corpus callosum," is published in the Aug. 29 issue of The Journal of Neuroscience. Other study authors are Vimal Selvaraj of Cornell University; Kouji Wakayama of UC Davis and the University of Tokyo; Lori Orosco, Eunyoung Lee, Fuzheng Guo, Jordan Lang, Makoto Horiuchi, Konstantios Zarbalis, Takayki Itoh and Wenbin Deng of UC Davis; and Susan Crawford of Northwestern University.
The study was funded by the National Institutes of Health (NIH Grant RO1 NS025044), National Multiple Sclerosis Society, Shriners Hospitals for Children and a postdoctoral fellowship grant to Sohn from the California Institute for Regenerative Medicine.