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Dr. Skoff. |
Vital to all vertebrates, oligodendrocytes are the supporting cells that ensheathe the axons of nerves. Without these cells, axons do not conduct electrical impulses properly, and this causes the symptoms of the human disease multiple sclerosis. Survival of oligodendrocytes is dependent upon a protein they make called proteolipid proteins (PLPs). Strangely, even seemingly insubstantial changes to the PLPs, such as conservative amino acid substitutions or a modest overexpression of this myelin protein, are lethal to animals and humans.
With a $900,000, four-year grant from the National Institutes of Health, Robert Skoff, PhD, professor of anatomy and cell biology, and his co-investigator Leon Carlock, PhD, associate professor in the Center for Molecular Medicine and Genetics, are investigating the mechanisms underlying the role of PLPs in oligodendrocyte death.
For this research project, they are studying the ubiquitin-proteasome complex, which is a major player in protein degradation. Ubiquitin is a small protein that links to the proteins targeted for degradation. "The ubiquitin-proteasome system cannot degrade the mutant proteolipid protein, which we think activates the programmed cell death cascade," explained Dr. Skoff.
"We will investigate--using tissue culture systems--how normal and mutant PLP proteins are processed by the ubiquitin-proteasome system and how oligodendrocyte death is induced," said Dr. Carlock. In particular, Drs. Skoff and Carlock, along with their research teams, will examine the molecular consequences of specific PLP mutations in programmed cell death; why overexpression of the normal PLP protein produces cell death; and what role the ubiquitin-proteasome complex plays in regulating protein degradation and cell death.
"By understanding the steps that cause death of oligodendrocytes, we should be able to develop therapies that prevent their death and this, in turn, could lead to treatment of certain human nervous system diseases," said