Neurology Central

Newly uncovered astrocyte pathway could have key role in neurological disorders

A ‘hidden’ pathway at work within the nuclei of astrocyte cells has recently been uncovered by an international team of researchers. This nuclear process is involved in the regulation of TGF-beta signaling and suggests that these glial cells could be involved in many neurological disorders. The results appeared this week in Nature Neuroscience.

“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,” commented senior author of the study Katerina Akassoglou (Gladstone Institute for Neurological Disease, University of California, San Francisco; CA, USA).

A number of neurological disorders, including Alzheimer’s disease and brain injury, have been previously associated with abnormally high levels of TGF-beta. Also previously described is the ability of astrocytes to produce higher levels of p75 neurotrophin receptor (p75NTR) – a protein that assists in the detection of growth factors – following brain injury. In reaction to TGF-beta, astrocytes are also known to change their shape and secrete proteins that modify neuronal activity.

In this study, Akassoglou and her team demonstrated that deletion of the p75NTR gene prevented hydrocephalus in mice with astrocytes engineered to produce higher levels of TGF-beta. Deletion of p75NTR also stopped these engineered astrocytes forming scars after injuries and restored gamma oscillations – patterns of neuronal activity associated with learning and memory.

Furthermore, treatment of astrocytes with TGF-beta allowed some of the p75NTR protein to bind to nucleoporins; a process that in turn appeared to enhance the passage of molecules into the nucleus and enabled astrocytes to enter a reactive state.

Observing the astrocyte nucleus under a high-resolution microscope, it was noted that the nuclear pores of cells that did not have the p75NTR gene were slightly enlarged in comparison to in normal cells. When astrocytes were treated with TGF-beta, p75NTR proteins bound to nucleoporins to open the pores. Smad2, which is essential for TGF-beta to exert its effects on astrocytes, was then able to enter the nucleus. The elimination of p75NTR from astrocytes blocked the transport of Smad2 into the nucleus.

“Nuclear pores are gatekeepers and p75NTR appears to be the key to unlocking particular gates,” continued Akassoglou. “We discovered novel roles for both players and will continue to study how the nuclear pore complex controls neuronal development and disease.”

“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,” commented Jill Morris of the NIH’s National Institute of Neurological Disorders and Stroke.

Source: NIH press release: