Neurology: Study Examines Possible Role Of Glial Brain Cells In Neurological Disorders
New findings published in the journal Nature Neuroscience show that the passage of molecules through the nucleus of a star-shaped brain cell, also called an astrocyte, may play a critical role in health and disease.
"Unexpectedly we may have discovered a hidden pathway to understanding how astrocytes respond to injury and control brain processes. The pathway may be common to many brain diseases and we're just starting to follow it," said Katerina Akassoglou, Ph.D., a senior investigator at the Gladstone Institute for Neurological Disease, a professor of neurology at the University of California, San Francisco, and a senior author of the study.
Some neurological disorders are linked to higher than normal brain levels of the growth factor TGF-beta, including Alzheimer's disease and brain injury. As previous studies have shown that after brain injuries, astrocytes produce greater amounts of p75 neurotrophin receptors (p75NTR)--a protein that helps cells detect growth factors--researchers also found that cells react to TGF-beta by changing their shapes and secreting proteins that alter neuronal activity.
Findings revealed that eliminating the p75NTR gene worked to prevent hydrocephalus--a disorder that fills the brain with excess cerebral spinal fluid--eliminating the p75NTR gene that also prevents astrocytes in the brains of the mice from forming scars after injuries and restored gamma oscillations, which are patterns of neuronal activity associated with learning and memory. The cell nucleus is a group of chromosomes that come in a protective fatty membrane.
In this study, researchers found that treating astrocytes with TGF-beta freed a small piece of the p75NTR protein to bind to nucleoporins--a group of proteins that regulate the passage of molecules in and out of the nucleus. Study results revealed that the binding helped to enhance the flow of certain critical molecules in the nucleus and enable astrocytes to enter a reactive state.
"This research highlights the importance of the nuclear pore complex in the brain and raises the possibility that it may be a target for treating a wide range of neurological disorders," Jill Morris, Ph.D., program director at the NIH's National Institute of Neurological Disorders and Stroke (NINDS), added.
From there, scientists used high-resolution microscopes to examine the astrocyte nucleus in action. Nuclear pores that did not have the p75NTR gene were slightly larger than normal. When the scientists treated astrocytes with TGF-beta, they saw p75NTR proteins bind to nucleoporins and open the pores, which allowed transport into the nucleus of a protein known as Smad2. This is essential for TGF-beta to exert its effects on astrocytes. In other experiments, the scientists showed that eliminating p75NTR from astrocytes blocked the transport of Smad2 into the nucleus.
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