CNTF, a glial cytokine that rescues neurons

Among the proteins identified as neurotrophic factors, based on their capac ity to rescue neurons during development as well as in adulthood, the cilia ry neurotrophic factor (CNTF) holds a special place, and has already been u sed repeatedly in clinical therapeutic trials for amyotrophic lateral scler osis and Huntington's disease. It is thus a paradox, that very little is kn own about this cytokine which belongs to the IL-6 family. In adults, CNTF i s massively synthesized by glial cells, astrocytes in the central nervous s ystem and Schwann cells in the periphery. However, its secretory pathways h ave not been described, nor is it known if it is really secreted. Indeed, t here is no signal peptide in its amino acid sequence, and the molecule is n ot detected in the supernatant of astroglial of Schwann cell cultures. Neve rtheless, the a subunit, which associates with the dimeric LIF receptor to form its trimeric receptor, is present on a large number of neurons and mus cle fibers, but not on astrocytes. In addition, under certain conditions, t he CNTF can also affect cells that only express the two LIF receptor subuni ts, in the absence of the a chain. The physiological roles of CNTF have als o remained elusive since its absence, in knock-out mice as well as in human s, has only modest consequences, if any, on neurons. When administered into the brain, or added to the culture medium, CNTF provokes astroglial activa tion. Finally, despite well reproducible neuroprotective effects described using various experimental animals, including non-human primates, clinical trials of neuroprotection using CNTF have so far been unsuccessful, althoug h these failures may be due to the delivery systems rather than to the fact or itself.