|M.Sc Student||Kupershmidt Lana|
|Subject||The Neuroprotective Role of Activin as an Antiapoptotic|
|Department||Department of Medicine||Supervisor||Professor Zeev Blumenfeld|
|Full Thesis text|
Activin is a member of the transforming growth factor (TGF) -b superfamily which comprises a growing list of multifunctional proteins that function as modulators of cell proliferation, differentiation, hormone secretion and neuronal survival. This study examined the neuroprotective effect of Activin A and B in serum withdrawal and oxidative stress apoptotic cellular models and investigated the expression of pro- and anti-apoptotic proteins, which may account for the mechanism of Activin-induced neuroprotection. We report that recombinant Activin A and B are neuroprotective against serum deprivation- and toxin- (either the parkinsonism-inducing neurotoxin, 6-hydroxydopamine (6-OHDA) or the peroxynitrite donor, SIN-1) induced neuronal death in human SH-SY5Y neuroblastoma cells. Furthermore, we demonstrate, for the first time, that transient transfection with Activin βA or βB significantly protect SH-SY5Y and rat pheochromocytoma PC12 cells against serum withdrawal- induced apoptosis. This survival effect of Activin A and B involved inhibition of caspase-3 activation, reduction of cleaved poly-ADP ribose polymerase (PARP) and phosphorylated H2A.X protein levels, elevation of tyrosine hydroxylase , and is mediated by the Bcl-2 family members. Activin βA and βB subunits overexpression abolished serum free-mediated decrease in Bcl-2 and Bcl-xL levels, as well as serum free-mediated increase in Bax and Bad levels. The protective effect of Activin on apoptosis was antagonized by cotreatment with the Activin-binding protein Follistatin and anti-βA and -βB Activin antibodies in serum deprived SH-SY5Y and PC12 cells transfected with plasmids, containing βA or βB subunits, further illustrating the crucial role of Activin in neuronal survival..
These results indicate that both Activin-A and -B share the potential to induce neuroprotective activity and thus may have positive impact on aging and neurodegenerative diseases to retard the accelerated rate of neuronal degeneration.